Diketo substituted pyrrolo[2,3-C]pyridines

ABSTRACT

Compounds having drug and bio-affecting properties, their pharmaceutical compositions and methods of use are set forth. In particular, diketo fused azolopiperidine and azolopiperazine derivatives of Formula I: 
                         
that possess unique antiviral activity are provided. These compounds are useful for the treatment of HIV and AIDS.

CROSS-REFERENCE TO RELATED APPLICATION

This Divisional application claims the benefit of U.S. Ser. No.12/490,714 filed Jun. 24, 2009, now allowed, which in turn claims thebenefit of U.S. Provisional Application Ser. No. 61/075,374 filed Jun.25, 2008.

FIELD OF THE INVENTION

This invention provides compounds having drug and bio-affectingproperties, their pharmaceutical compositions and methods of use. Inparticular, the disclosure is directed to diketo fused azolopiperidineand azolopiperazine derivatives that possess unique antiviral activity.More particularly, the present disclosure relates to compounds usefulfor the treatment of HIV and AIDS.

BACKGROUND OF THE INVENTION

HIV-1 (human immunodeficiency virus-1) infection remains a major medicalproblem, with an estimated 45 million people infected worldwide at theend of 2007. The number of cases of HIV and AIDS (acquiredimmunodeficiency syndrome) has risen rapidly. In 2005, approximately 5.0million new infections were reported, and 3.1 million people died fromAIDS. Currently available drugs for the treatment of HIV includenucleoside reverse transcriptase (RT) inhibitors or approved single pillcombinations: zidovudine (or AZT or RETROVIR®), didanosine (or VIDEX®),stavudine (or ZERIT®), lamivudine (or 3TC or EPIVIR®), zalcitabine (orDDC or HIVID®), abacavir succinate (or ZIAGEN®), tenofovir disoproxilfumarate salt (or VIREAD®), emtricitabine (or FTC—EMTRIVA®), COMBIVIR®(contains-3TC plus AZT), TRIZIVIR® (contains abacavir, lamivudine, andzidovudine), Epzicom (contains abacavir and lamivudine), TRUVADA®(contains VIREAD® and EMTRIVA®); non-nucleoside reverse transcriptaseinhibitors: nevirapine (or VIRAMUNE®), delavirdine (or RESCRIPTOR®) andefavirenz (or SUSTIVA®), Atripla (TRUVADA®+SUSTIVA®), and etravirine,and peptidomimetic protease inhibitors or approved formulations:saquinavir, indinavir, ritonavir, nelfinavir, amprenavir, lopinavir,KALETRA® (lopinavir and Ritonavir), darunavir, atazanavir (REYATAZ®) andtipranavir (APTIVUS®), and integrase inhibitors such as raltegravir(Isentress), and entry inhibitors such as enfuvirtide (T-20) (FUZEON®)and maraviroc (Selzentry).

Each of these drugs can only transiently restrain viral replication ifused alone. However, when used in combination, these drugs have aprofound effect on viremia and disease progression. In fact, significantreductions in death rates among AIDS patients have been recentlydocumented as a consequence of the widespread application of combinationtherapy. However, despite these impressive results, 30 to 50% ofpatients may ultimately fail combination drug therapies. Insufficientdrug potency, non-compliance, restricted tissue penetration anddrug-specific limitations within certain cell types (e.g., mostnucleoside analogs cannot be phosphorylated in resting cells) mayaccount for the incomplete suppression of sensitive viruses.Furthermore, the high replication rate and rapid turnover of HIV-1combined with the frequent incorporation of mutations, leads to theappearance of drug-resistant variants and treatment failures whensub-optimal drug concentrations are present. Therefore, novel anti-HIVagents exhibiting distinct resistance patterns, and favorablepharmacokinetic as well as safety profiles are needed to provide moretreatment options. Improved HIV fusion inhibitors and HIV entrycoreceptor antagonists are two examples of new classes of anti-HIVagents further being studied by a number of investigators.

HIV attachment inhibitors are a novel subclass of antiviral compoundsthat bind to the HIV surface glycoprotein gp120, and interfere with theinteraction between the surface protein gp120 and the host cell receptorCD4. Thus, they prevent HIV from attaching to the human CD4 T-cell, andblock HIV replication in the first stage of the HIV life cycle. Theproperties of HIV attachment inhibitors have been improved in an effortto obtain compounds with maximized utility and efficacy as antiviralagents. A disclosure describing indoles of which the structure shownbelow for BMS-705 is representative, has been disclosed (AntiviralIndoleoxoacetyl piperazine Derivatives).

Two other compounds, referred to in the literature as BMS-806 andBMS-043 have been described in both the academic and patent art:

Some description of their properties in human clinical trials has beendisclosed in the literature.

It should be noted that in all three of these structures, a piperazineamide (in these three structures a piperazine phenyl amide) is presentand this group is directly attached to an oxoacetyl moiety. Theoxoacetyl group is attached at the 3-position of 4-fluoro indole inBMS-705 and to the 3 position of substituted azaindoles in BMS-806 andBMS-043.

In an effort to obtain improved anti-HIV compounds, later publicationsdescribed in part, modified substitution patterns on the indoles andazaindoles. Examples of such efforts include: (1) novel substitutedindoleoxoacetic piperazine derivatives, (2) substitutedpiperazinyloxoacetylindole derivatives, and (3) substitutedazaindoleoxoacetic piperazine derivatives.

Replacement of these groups with other heteroaromatics or substitutedheteroaromatics or bicyclic hydrocarbons was also shown to be feasible.Examples include: (1) indole, azaindole and related heterocyclicamidopiperazine derivatives; (2) bicyclo 4.4.0 antiviral derivatives;and (3) diazaindole derivatives.

A select few replacements for the piperazine amide portion of themolecules have also been described in the art and among these examplesare (1) some piperidine alkenes; (2) some pyrrolidine amides; (3) someN-aryl or heteroaryl piperazines; (4) some piperazinyl ureas; and (5)some carboline containing compounds.

Method(s) for preparing prodrugs for this class of compounds aredisclosed in Prodrugs of piperazine and Substituted Piperidine AntiviralAgents (Ueda et al., U.S. non-provisional application Ser. No.11/066,745, filed Feb. 25, 2005 or U.S. Publication No. 2005/0209246 orWO 2005/090367 A1).

A published PCT patent application WO 2003/103607 A1 (Jun. 11, 2003)disclosures an assay useful for assaying some HIV inhibitors.

Several published patent applications describe combination studies withpiperazine benzamide inhibitors, for example, U.S. Publication No.2005/0215543 (WO 2005/102328 A1), U.S. Publication No. 2005/0215544 (WO2005/102391 A1), and U.S. Publication No. 2005/0215545 (WO 2005/102392A2).

A publication on new compounds in this class of attachment inhibitors(Wang, J. et al., Org. Biol. Chem., 3:1781-1786 (2005)) and a patentapplication on some more remotely related compounds have appeared WO2005/016344 published on Feb. 24, 2005.

Published patent applications WO 2005/016344 and WO 2005/121094 alsodescribe piperazine derivatives which are HIV inhibitors. Otherreferences in the HIV attachment area include U.S. Publication Nos.2007/0155702, 2007/0078141 and 2007/0287712, WO 2007/103456, as well asU.S. Pat. Nos. 7,348,337 and 7,354,924. A literature reference is J.Med. Chem., 50:6535 (2007).

What is therefore needed in the art are new HIV attachment inhibitorcompounds, and compositions thereof, which are efficacious against HIVinfection. The compounds described in the foregoing references arestructurally distinct from the compounds of the present inventionhereinafter described.

SUMMARY OF THE INVENTION

The present invention provides compounds of Formula I below, thepharmaceutically acceptable salts and/or solvates (e.g., hydrates)thereof, their pharmaceutical formulations, and their use in patientssuffering from or susceptible to a virus such as HIV. The compounds ofFormula I, their pharmaceutically acceptable salts and/or solvates areeffective antiviral agents, particularly as inhibitors of HIV. They areuseful for the treatment of HIV and AIDS.

One embodiment of the present invention is directed to a compound ofFormula I, including pharmaceutically acceptable salts thereof:

wherein A is selected from the group consisting of:

wherein B is selected from the group consisting of:

and further wherein

a is selected from the group consisting of H, halogen and methoxy;

b and c are selected from the group consisting of H and halogen;

d is selected from the group consisting of H, halogen, methoxy and GroupC;

e is H;

f and g are selected from the group consisting of H, (C₁-C₄) alkyl, and(C₃-C₆) cycloalkyl group, and wherein said alkyl or cycloalkyl group isoptionally substituted with one to three substitutions selected from thegroup of F, OH, OR, NR₁R₂, COOR, and CONR₁R₂;

and wherein f and g can be connected by carbon, oxygen, nitrogen orsulfur atom to form a ring;

h and i are selected from the group consisting of H, (C₁-C₄) alkyl, and(C₃-C₆) cycloalkyl group, wherein said alkyl or cycloalkyl group isoptionally substituted with one to three substitutions selected from thegroup of F, OH, OR, NR₁R₂, COOR, and CONR₁R₂;

and wherein h and i can be connected by a carbon, oxygen, nitrogen orsulfur atom to form a ring;

j and k are selected from the group consisting of H, F, (C₁-C₄) alkyl,and (C₃-C₆) cycloalkyl group, and wherein said alkyl or cycloalkyl groupis optionally substituted with one to three substitutions selected fromthe group of F, OH, OR, NR₁R₂, COOR, and CONR₁R₂;

and wherein j and k can be connected by carbon, oxygen, nitrogen orsulfur atom to form a ring;

and further wherein j+k is C═O;

l and m are selected from the group consisting of H, OH, (C₁-C₄) alkyloptionally substituted with one to three substitutions selected from F,OH, OR, NR₁R₂, COOR, CONR₁R₂, (C₃-C₆) cycloalkyl optionally substitutedwith one to three substitutions selected from F, OH, OR, NR₁R₂, COOR,CONR₁R₂, OR, halogen (attached to carbon only), OR, NR₁R₂, COOR,CONR₁R₂, and Group D;

n and o are selected from the group consisting of H, (C₁-C₄) alkyloptionally substituted with one to three substitutions selected from F,OH, OR, NR₁R₂, COOR, CONR₁R₂, (C₃-C₆) cycloalkyl optionally substitutedwith one to three substitutions (selected from F, OH, OR, NR₁R₂, COOR,CONR₁R₂), COOR, CONR₁R₂ and Group D;

Ar is selected from the group consisting of phenyl and heteroaryl;wherein said phenyl and heteroaryl are independently optionallysubstituted with one to three same or different halogens or from one tothree same or different substituents selected from Group E; heteroarylis selected from the group consisting of pyridinyl, pyrazinyl,pyridazinyl, pyrimidinyl, furanyl, thienyl, thiazolyl, imidazolyl,oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, and triazolyl;

Group C is selected from the group consisting of COOR, CONR₁R₂, andGroup D;

Group D is selected from the group consisting of phenyl and heteroaryl;wherein said phenyl and heteroaryl are independently optionallysubstituted with one to three same or different halogens or from one tothree same or different substituents selected from Group E; heteroarylis selected from the group consisting of pyridinyl, pyrazinyl,pyridazinyl, pyrimidinyl, furanyl, thienyl, thiazolyl, imidazolyl,oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, and triazolyl;

Group E is selected from the group consisting of OH, OR, NR₁R₂, CN,COOR, CONR₁R₂, (C₁-C₄) alkyl, (C₃-C₆) cycloalkyl, and wherein said alkylor cycloalkyl group is optionally substituted with one to threesubstitutions selected from the group of F, OH, OR, NR₁R₂, COOR, andCONR₁R₂;

R, R₁ and R₂ are independently H, (C₁-C₄) alkyl, (C₃-C₆) cycloalkylgroup; and wherein R₁ and R₂ can be connected by carbon, oxygen,nitrogen or sulfur atom to form a ring.

Another embodiment of the present invention is directed to a method fortreating mammals infected with a virus, especially wherein said virus isHIV, comprising administering to said mammal an antiviral effectiveamount of a compound of Formula I above, and one or morepharmaceutically acceptable carriers, excipients or diluents.Optionally, the compound of Formula I can be administered in combinationwith an antiviral effective amount of an AIDS treatment agent selectedfrom the group consisting of: (a) an AIDS antiviral agent; (b) ananti-infective agent; (c) an immunomodulator; and (d) other HIV entryinhibitors.

Another embodiment of the present invention is a pharmaceuticalcomposition comprising an antiviral effective amount of a compound ofFormula I and one or more pharmaceutically acceptable carriers,excipients, diluents and optionally in combination with an antiviraleffective amount of an AIDS treatment agent selected from the groupconsisting of: (a) an AIDS antiviral agent; (b) an anti-infective agent;(c) an immunomodulator; and (d) other HIV entry inhibitors.

In another embodiment of the invention there is provided one or moremethods for making the compounds of Formula I.

The present invention is directed to these, as well as other importantends, hereinafter described.

DETAILED DESCRIPTION OF THE EMBODIMENTS

Since the compounds of the present disclosure may possess asymmetriccenters and therefore occur as mixtures of diastereomers andenantiomers, the present disclosure includes the individualdiastereoisomeric and enantiomeric forms of the compounds of Formula Iin addition to the mixtures thereof

Definitions

Unless otherwise specifically set forth elsewhere in the application,one or more of the following terms may be used herein, and shall havethe following meanings:

The term “C₁₋₆ alkyl” as used herein and in the claims (unless specifiedotherwise) mean straight or branched chain alkyl groups such as methyl,ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, amyl, hexyl and thelike.

“C₁-C₄-fluoroalkyl” refers to F-substituted C₁-C₄ alkyl wherein at leastone H atom is substituted with F atom, and each H atom can beindependently substituted by F atom;

“Halogen” refers to chlorine, bromine, iodine or fluorine.

An “aryl” or “Ar” group refers to an all carbon monocyclic or fused-ringpolycyclic (i.e., rings which share adjacent pairs of carbon atoms)groups having a completely conjugated pi-electron system. Examples,without limitation, of aryl groups are phenyl, napthalenyl andanthracenyl. The aryl group may be substituted or unsubstituted. Whensubstituted the substituted group(s) is preferably one or more selectedfrom alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy,alkoxy, aryloxy, heteroaryloxy, heteroalicycloxy, thiohydroxy,thioaryloxy, thioheteroaryloxy, thioheteroalicycloxy, cyano, halogen,nitro, carbonyl, O-carbamyl, N-carbamyl, C-amido, N-amido, C-carboxy,O-carboxy, sulfinyl, sulfonyl, sulfonamido, trihalomethyl, ureido, aminoand —NR^(x)R^(y), wherein R^(x) and R^(y) are independently selectedfrom the group consisting of hydrogen, alkyl, cycloalkyl, aryl,carbonyl, C-carboxy, sulfonyl, trihalomethyl, and, combined, a five- orsix-member heteroalicyclic ring.

As used herein, a “heteroaryl” group refers to a monocyclic or fusedring (i.e., rings which share an adjacent pair of atoms) group having inthe ring(s) one or more atoms selected from the group consisting ofnitrogen, oxygen and sulfur and, in addition, having a completelyconjugated pi-electron system. Unless otherwise indicated, theheteroaryl group may be attached at either a carbon or nitrogen atomwithin the heteroaryl group. It should be noted that the term heteroarylis intended to encompass an N-oxide of the parent heteroaryl if such anN-oxide is chemically feasible as is known in the art. Examples, withoutlimitation, of heteroaryl groups are furyl, thienyl, benzothienyl,thiazolyl, imidazolyl, oxazolyl, oxadiazolyl, thiadiazolyl,benzothiazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl,pyrrolyl, pyranyl, tetrahydropyranyl, pyrazolyl, pyridyl, pyrimidinyl,quinolinyl, isoquinolinyl, purinyl, carbazolyl, benzoxazolyl,benzimidazolyl, indolyl, isoindolyl, pyrazinyl. diazinyl, pyrazine,triazinyl, tetrazinyl, and tetrazolyl. When substituted the substitutedgroup(s) is preferably one or more selected from alkyl, cycloalkyl,aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy,heteroaryloxy, heteroalicycloxy, thioalkoxy, thiohydroxy, thioaryloxy,thioheteroaryloxy, thioheteroalicycloxy, cyano, halogen, nitro,carbonyl, O-carbamyl, N-carbamyl, C-amido, N-amido, C-carboxy,O-carboxy, sulfinyl, sulfonyl, sulfonamido, trihalomethyl, ureido,amino, and —NR^(x)R^(y), wherein R^(x) and R^(y) are as defined above.

As used herein, a “heteroalicyclic” group refers to a monocyclic orfused ring group having in the ring(s) one or more atoms selected fromthe group consisting of nitrogen, oxygen and sulfur. Rings are selectedfrom those which provide stable arrangements of bonds and are notintended to encompass systems which would not exist. The rings may alsohave one or more double bonds. However, the rings do not have acompletely conjugated pi-electron system. Examples, without limitation,of heteroalicyclic groups are azetidinyl, piperidyl, piperazinyl,imidazolinyl, thiazolidinyl, 3-pyrrolidin-1-yl, morpholinyl,thiomorpholinyl and tetrahydropyranyl. When substituted the substitutedgroup(s) is preferably one or more selected from alkyl, cycloalkyl,aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy,heteroaryloxy, heteroalicycloxy, thiohydroxy, thioalkoxy, thioaryloxy,thioheteroaryloxy, thioheteroalicycloxy, cyano, halogen, nitro,carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl,N-thiocarbamyl, C-amido, C-thioamido, N-amido, C-carboxy, O-carboxy,sulfinyl, sulfonyl, sulfonamido, trihalomethanesulfonamido,trihalomethanesulfonyl, silyl, guanyl, guanidino, ureido, phosphonyl,amino and —NR^(x)R^(y), wherein R^(x) and R^(y) are as defined above.

An “alkyl” group refers to a saturated aliphatic hydrocarbon includingstraight chain and branched chain groups. Preferably, the alkyl grouphas 1 to 20 carbon atoms (whenever a numerical range; e.g., “1-20”, isstated herein, it means that the group, in this case the alkyl group maycontain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc. up to andincluding 20 carbon atoms). More preferably, it is a medium size alkylhaving 1 to 10 carbon atoms. Most preferably, it is a lower alkyl having1 to 4 carbon atoms. The alkyl group may be substituted orunsubstituted. When substituted, the substituent group(s) is preferablyone or more individually selected from trihaloalkyl, cycloalkyl, aryl,heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, heteroaryloxy,heteroalicycloxy, thiohydroxy, thioalkoxy, thioaryloxy,thioheteroaryloxy, thioheteroalicycloxy, cyano, halo, nitro, carbonyl,thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl,C-amido, C-thioamido, N-amido, C-carboxy, O-carboxy, sulfinyl, sulfonyl,sulfonamido, trihalomethanesulfonamido, trihalomethanesulfonyl, andcombined, a five- or six-member heteroalicyclic ring.

A “cycloalkyl” group refers to an all-carbon monocyclic or fused ring(i.e., rings which share and adjacent pair of carbon atoms) groupwherein one or more rings does not have a completely conjugatedpi-electron system. Examples, without limitation, of cycloalkyl groupsare cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane,cyclohexene, cycloheptane, cycloheptene and adamantane. A cycloalkylgroup may be substituted or unsubstituted. When substituted, thesubstituent group(s) is preferably one or more individually selectedfrom alkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy,heteroaryloxy, heteroalicycloxy, thiohydroxy, thioalkoxy, thioaryloxy,thioheteroaryloxy, thioheteroalicycloxy, cyano, halo, nitro, carbonyl,thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl,C-amido, C-thioamido, N-amido, C-carboxy, O-carboxy, sulfinyl, sulfonyl,sulfonamido, trihalomethanesulfonamido, trihalomethanesulfonyl, silyl,guanyl, guanidino, ureido, phosphonyl, amino and —NR^(x)R^(y) with R^(x)and R^(y) as defined above.

An “alkenyl” group refers to an alkyl group, as defined herein, havingat least two carbon atoms and at least one carbon-carbon double bond.

An “alkynyl” group refers to an alkyl group, as defined herein, havingat least two carbon atoms and at least one carbon-carbon triple bond.

A “hydroxy” group refers to an —OH group.

An “alkoxy” group refers to both an —O-alkyl and an —O-cycloalkyl groupas defined herein.

An “aryloxy” group refers to both an —O-aryl and an —O-heteroaryl group,as defined herein.

A “heteroaryloxy” group refers to a heteroaryl-O— group with heteroarylas defined herein.

A “heteroalicycloxy” group refers to a heteroalicyclic-O— group withheteroalicyclic as defined herein.

A “thiohydroxy” group refers to an —SH group.

A “thioalkoxy” group refers to both an S-alkyl and an —S-cycloalkylgroup, as defined herein.

A “thioaryloxy” group refers to both an —S-aryl and an —S-heteroarylgroup, as defined herein.

A “thioheteroaryloxy” group refers to a heteroaryl-S— group withheteroaryl as defined herein.

A “thioheteroalicycloxy” group refers to a heteroalicyclic-S— group withheteroalicyclic as defined herein.

A “carbonyl” group refers to a —C(═O)—R″ group, where R″ is selectedfrom the group consisting of hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) andheteroalicyclic (bonded through a ring carbon), as each is definedherein.

An “aldehyde” group refers to a carbonyl group where R″ is hydrogen.

A “thiocarbonyl” group refers to a —C(═S)—R″ group, with R″ as definedherein.

A “Keto” group refers to a —CC(═O)C— group wherein the carbon on eitheror both sides of the C═O may be alkyl, cycloalkyl, aryl or a carbon of aheteroaryl or heteroalicyclic group.

A “trihalomethanecarbonyl” group refers to a Z₃CC(═O)— group with said Zbeing a halogen.

A “C-carboxy” group refers to a —C(═O)O—R″ groups, with R″ as definedherein.

An “O-carboxy” group refers to a R″C(—O)O-group, with R″ as definedherein.

A “carboxylic acid” group refers to a C-carboxy group in which R″ ishydrogen.

A “trihalomethyl” group refers to a —CZ₃, group wherein Z is a halogengroup as defined herein.

A “trihalomethanesulfonyl” group refers to an Z₃CS(═O)₂— groups with Zas defined above.

A “trihalomethanesulfonamido” group refers to a Z₃CS(═O)₂NR^(x)— groupwith Z as defined above and R^(x) being H or (C₁₋₆)alkyl.

A “sulfinyl” group refers to a —S(═O)—R″ group, with R″ being(C₁₋₆)alkyl.

A “sulfonyl” group refers to a —S(═O)₂R″ group with R″ being(C₁₋₆)alkyl.

A “S-sulfonamido” group refers to a —S(═O)₂NR^(x)R^(y), with R^(x) andR^(y) independently being H or (C₁₋₆)alkyl.

A “N-Sulfonamido” group refers to a R″S(═O)₂NR_(x)— group, with R_(x)being H or (C₁₋₆)alkyl.

A “O-carbamyl” group refers to a —OC(═O)NR^(x)R^(y) group, with R^(x)and R^(y) independently being H or (C₁₋₆)alkyl.

A “N-carbamyl” group refers to a R^(x)OC(═O)NR^(y) group, with R^(x) andR^(y) independently being H or (C₁₋₆)alkyl.

A “O-thiocarbamyl” group refers to a —OC(═S)NR^(x)R^(y) group, withR^(x) and R^(y) independently being H or (C₁₋₆)alkyl.

A “N-thiocarbamyl” group refers to a R^(x)OC(═S)NR^(y)— group, withR^(x) and R^(y) independently being H or (C₁₋₆)alkyl.

An “amino” group refers to an —NH₂ group.

A “C-amido” group refers to a —C(═O)NR^(x)R^(y) group, with R^(x) andR^(y) independently being H or (C₁₋₆)alkyl.

A “C-thioamido” group refers to a —C(═S)NR^(x)R^(y) group, with R^(x)and R^(y) independently being H or (C₁₋₆)alkyl.

A “N-amido” group refers to a R^(x)C(═O)NR^(y)— group, with R^(x) andR^(y) independently being H or (C₁₋₆)alkyl.

An “ureido” group refers to a —NR^(x)C(═O)NR^(y)R^(y2) group, withR^(x), R^(y), and R^(y2) independently being H or (C₁₋₆)alkyl.

A “guanidino” group refers to a —R^(x)NC(═N)NR^(y)R^(y2) group, withR^(x), R^(y), and R^(y2) independently being H or (C₁₋₆)alkyl.

A “guanyl” group refers to a R^(x)R^(y)NC(═N)— group, with R^(x) andR^(y) independently being H or (C₁₋₆)alkyl.

A “cyano” group refers to a —CN group.

A “silyl” group refers to a —Si(R″)₃, with R″ being (C₁₋₆)alkyl orphenyl.

A “phosphonyl” group refers to a P(═O)(OR^(x))₂ with R^(x) being(C₁₋₆)alkyl.

A “hydrazino” group refers to a —NR^(x)NR^(y)R^(y2) group, with R^(x),R^(y), and R^(y2) independently being H or (C₁₋₆)alkyl.

A “4, 5, or 6 membered ring cyclic N-lactam” group refers to

Any two adjacent R groups may combine to form an additional aryl,cycloalkyl, heteroaryl or heterocyclic ring fused to the ring initiallybearing those R groups.

It is known in the art that nitrogen atoms in heteroaryl systems can be“participating in a heteroaryl ring double bond”, and this refers to theform of double bonds in the two tautomeric structures which comprisefive-member ring heteroaryl groups. This dictates whether nitrogens canbe substituted as well understood by chemists in the art. The disclosureand claims of the present disclosure are based on the known generalprinciples of chemical bonding. It is understood that the claims do notencompass structures known to be unstable or not able to exist based onthe literature.

Pharmaceutically acceptable salts and prodrugs of compounds disclosedherein are within the scope of this disclosure. The term“pharmaceutically acceptable salt” as used herein and in the claims isintended to include nontoxic base addition salts. Suitable salts includethose derived from organic and inorganic acids such as, withoutlimitation, hydrochloric acid, hydrobromic acid, phosphoric acid,sulfuric acid, methanesulfonic acid, acetic acid, tartaric acid, lacticacid, sulfinic acid, citric acid, maleic acid, fumaric acid, sorbicacid, aconitic acid, salicylic acid, phthalic acid, and the like. Theterm “pharmaceutically acceptable salt” as used herein is also intendedto include salts of acidic groups, such as a carboxylate, with suchcounterions as ammonium, alkali metal salts, particularly sodium orpotassium, alkaline earth metal salts, particularly calcium ormagnesium, and salts with suitable organic bases such as loweralkylamines (methylamine, ethylamine, cyclohexylamine, and the like) orwith substituted lower alkylamines (e.g., hydroxyl-substitutedalkylamines such as diethanolamine, triethanolamine ortris(hydroxymethyl)-aminomethane), or with bases such as piperidine ormorpholine.

As stated above, the compounds of the invention also include “prodrugs”.The term “prodrug” as used herein encompasses both the term “prodrugesters” and the term “prodrug ethers”. The term “prodrug esters” asemployed herein includes esters and carbonates formed by reacting one ormore hydroxyls of compounds of Formula I with either alkyl, alkoxy, oraryl substituted acylating agents or phosphorylating agent employingprocedures known to those skilled in the art to generate acetates,pivalates, methylcarbonates, benzoates, amino acid esters, phosphates,half acid esters such as malonates, succinates or glutarates, and thelike. In certain embodiments, amino acid esters may be especiallypreferred.

Examples of such prodrug esters include

The term “prodrug ethers” include both phosphate acetals andO-glucosides. Representative examples of such prodrug ethers include

As set forth above, the invention is directed to compounds of Formula I,including pharmaceutically acceptable salts thereof:

wherein A is selected from the group consisting of:

wherein B is selected from the group consisting of:

and further wherein

a is selected from the group consisting of H, halogen and methoxy;

b and c are selected from the group consisting of H and halogen;

d is selected from the group consisting of H, halogen, methoxy and GroupC;

e is H;

f and g are selected from the group consisting of H, (C₁-C₄) alkyl, and(C₃-C₆) cycloalkyl group, and wherein said alkyl or cycloalkyl group isoptionally substituted with one to three substitutions selected from thegroup of F, OH, OR, NR₁R₂, COOR, and CONR₁R₂;

and wherein f and g can be connected by carbon, oxygen, nitrogen orsulfur atom to form a ring;

h and i are selected from the group consisting of H, (C₁-C₄) alkyl, and(C₃-C₆) cycloalkyl group. wherein said alkyl or cycloalkyl group isoptionally substituted with one to three substitutions selected from thegroup of F, OH, OR, NR₁R₂, COOR, and CONR₁R₂;

and wherein h and i can be connected by a carbon, oxygen, nitrogen orsulfur atom to form a ring;

j and k are selected from the group consisting of H, F, (C₁-C₄) alkyl,and (C₃-C₆) cycloalkyl group, and wherein said alkyl or cycloalkyl groupis optionally substituted with one to three substitutions selected fromthe group of F, OH, OR, NR₁R₂, COOR, and CONR₁R₂;

and wherein j and k can be connected by carbon, oxygen, nitrogen orsulfur atom to form a ring;

and further wherein j+k is C═O;

l and m are selected from the group consisting of H, OH, (C₁-C₄) alkyloptionally substituted with one to three substitutions selected from F,OH, OR, NR₁R₂, COOR, CONR₁R₂, (C₃-C₆) cycloalkyl optionally substitutedwith one to three substitutions selected from F, OH, OR, NR₁R₂, COOR,CON R₁R₂, OR, halogen (attached to carbon only), OR, NR₁R₂, COOR,CONR₁R₂, and Group D;

n and o are selected from the group consisting of H, (C₁-C₄) alkyloptionally substituted with one to three substitutions selected from F,OH, OR, NR₁R₂, COOR, CON R₁R₂, (C₃-C₆) cycloalkyl optionally substitutedwith one to three substitutions (selected from F, OH, OR, NR₁R₂, COOR,CONR₁R₂), COOR, CONR₁R₂ and Group D;

Ar is selected from the group consisting of phenyl and heteroaryl;wherein said phenyl and heteroaryl are independently optionallysubstituted with one to three same or different halogens or from one tothree same or different substituents selected from Group E; heteroarylis selected from the group consisting of pyridinyl, pyrazinyl,pyridazinyl, pyrimidinyl, furanyl, thienyl, thiazolyl, imidazolyl,oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, and triazolyl;

Group C is selected from the group consisting of COOR, CONR₁R₂, andGroup D;

Group D is selected from the group consisting of phenyl and heteroaryl;wherein said phenyl and heteroaryl are independently optionallysubstituted with one to three same or different halogens or from one tothree same or different substituents selected from Group E; heteroarylis selected from the group consisting of pyridinyl, pyrazinyl,pyridazinyl, pyrimidinyl, furanyl, thienyl, thiazolyl, imidazolyl,oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, and triazolyl;

Group E is selected from the group consisting of OH, OR, NR₁R₂, CN,COOR, CONR₁R₂, (C₁-C₄) alkyl, (C₃-C₆) cycloalkyl, and wherein said alkylor cycloalkyl group is optionally substituted with one to threesubstitutions selected from the group of F, OH, OR, NR₁R₂, COOR, andCONR₁R₂;

R, R₁ and R₂ are independently H, (C₁-C₄) alkyl, (C₃-C₆) cycloalkylgroup; and wherein R₁ and R₂ can be connected by carbon, oxygen,nitrogen or sulfur atom to form a ring.

More preferred compounds of the Formula I include those wherein A=

Also preferred compounds of the Formula I include those wherein B=

In another embodiment, both the preferred forms of A and B in thecompound of Formula I are as set forth above.

Particularly preferred compounds of the invention as part of Formula Iinclude the following:

The compounds of the present invention, according to all the variousembodiments described above, may be administered orally, parenterally(including subcutaneous injections, intravenous, intramuscular,intrasternal injection or infusion techniques), by inhalation spray, orrectally, and by other means, in dosage unit formulations containingnon-toxic pharmaceutically acceptable carriers, excipients and diluentsavailable to the skilled artisan. One or more adjuvants may also beincluded.

Thus, in accordance with the present disclosure, there is furtherprovided a method of treatment, and a pharmaceutical composition, fortreating viral infections such as HIV infection and AIDS. The treatmentinvolves administering to a patient in need of such treatment apharmaceutical composition which contains an antiviral effective amountof one or more of the compounds of Formula I, together with one or morepharmaceutically acceptable carriers, excipients or diluents. As usedherein, the term “antiviral effective amount” means the total amount ofeach active component of the composition and method that is sufficientto show a meaningful patient benefit, i.e., inhibiting, ameliorating, orhealing of acute conditions characterized by inhibition of the HIVinfection. When applied to an individual active ingredient, administeredalone, the term refers to that ingredient alone. When applied to acombination, the term refers to combined amounts of the activeingredients that result in the therapeutic effect, whether administeredin combination, serially or simultaneously. The terms “treat, treating,treatment” as used herein and in the claims means preventing,ameliorating or healing diseases associated with HIV infection.

The pharmaceutical compositions of the invention may be in the form oforally administrable suspensions or tablets; as well as nasal sprays,sterile injectable preparations, for example, as sterile injectableaqueous or oleaginous suspensions or suppositories. Pharmaceuticallyacceptable carriers, excipients or diluents may be utilized in thepharmaceutical compositions, and are those utilized in the art ofpharmaceutical preparations.

When administered orally as a suspension, these compositions areprepared according to techniques typically known in the art ofpharmaceutical formulation and may contain microcrystalline cellulosefor imparting bulk, alginic acid or sodium alginate as a suspendingagent, methylcellulose as a viscosity enhancer, and sweeteners/flavoringagents known in the art. As immediate release tablets, thesecompositions may contain microcrystalline cellulose, dicalciumphosphate, starch, magnesium stearate and lactose and/or otherexcipients, binders, extenders, disintegrants, diluents, and lubricantsknown in the art.

The injectable solutions or suspensions may be formulated according toknown art, using suitable non-toxic, parenterally acceptable diluents orsolvents, such as mannitol, 1,3-butanediol, water, Ringer's solution orisotonic sodium chloride solution, or suitable dispersing or wetting andsuspending agents, such as sterile, bland, fixed oils, includingsynthetic mono- or diglycerides, and fatty acids, including oleic acid.

The compounds of this disclosure can be administered orally to humans ina dosage range of 1 to 100 mg/kg body weight in divided doses, usuallyover an extended period, such as days, weeks, months, or even years. Onepreferred dosage range is 1 to 10 mg/kg body weight orally in divideddoses. Another preferred dosage range is 1 to 20 mg/kg body weight individed doses. It will be understood, however, that the specific doselevel and frequency of dosage for any particular patient may be variedand will depend upon a variety of factors including the activity of thespecific compound employed, the metabolic stability and length of actionof that compound, the age, body weight, general health, sex, diet, modeand time of administration, rate of excretion, drug combination, theseverity of the particular condition, and the host undergoing therapy.

Also contemplated herein are combinations of the compounds of Formula Iherein set forth, together with one or more agents useful in thetreatment of AIDS. For example, the compounds of this disclosure may beeffectively administered, whether at periods of pre-exposure and/orpost-exposure, in combination with effective amounts of the AIDSantivirals, immunomodulators, anti-infectives, or vaccines, such asthose in the following non-limiting table:

Drug Name Manufacturer Indication ANTIVIRALS 097 Hoechst/Bayer HIVinfection, AIDS, ARC (non-nucleoside reverse transcriptase (RT)inhibitor) Amprenavir GlaxoWellcome HIV infection, 141 W94 AIDS, ARC GW141 (protease inhibitor) Abacavir (1592U89) GlaxoWellcome HIV infection,GW 1592 AIDS, ARC (RT inhibitor) Acemannan Carrington Labs ARC (Irving,TX) Acyclovir Burroughs Wellcome HIV infection, AIDS, ARC, incombination with AZT AD-439 Tanox Biosystems HIV infection, AIDS, ARCAD-519 Tanox Biosystems HIV infection, AIDS, ARC Adefovir dipivoxilGilead Sciences HIV infection AL-721 Ethigen ARC, PGL (Los Angeles, CA)HIV positive, AIDS Alpha Interferon GlaxoWellcome Kaposi's sarcoma, HIVin combination with RETROVIR ® Ansamycin Adria Laboratories ARC LM 427(Dublin, OH) Erbamont (Stamford, CT) Antibody which Advanced BiotherapyAIDS, ARC neutralizes pH Concepts labile alpha aberrant (Rockville, MD)interferon AR177 Aronex Pharm HIV infection, AIDS, ARC Beta-fluoro-ddANat'l Cancer Institute AIDS-associated diseases BMS-234475 Bristol-MyersSquibb/ HIV infection, (CGP-61755) Novartis AIDS, ARC (proteaseinhibitor) CI-1012 Warner-Lambert HIV-1 infection Cidofovir GileadScience CMV retinitis, herpes, papillomavirus Curdlan sulfate AJI PharmaUSA HIV infection Cytomegalovirus MedImmune CMV retinitis immune globinCytovene Syntex Sight threatening Ganciclovir CMV peripheral CMVretinitis Darunavir Tibotec- J & J HIV infection, (Prezista) AIDS, ARC(protease inhibitor) Delaviridine Pharmacia-Upjohn HIV infection, AIDS,ARC (RT inhibitor) Dextran Sulfate Ueno Fine Chem. AIDS, ARC, HIV Ind.Ltd. (Osaka, positive Japan) asymptomatic ddC Hoffman-La Roche HIVinfection, AIDS, Dideoxycytidine ARC ddI Bristol-Myers Squibb HIVinfection, AIDS, Dideoxyinosine ARC; combination with AZT/d4T DMP-450AVID HIV infection, (Camden, NJ) AIDS, ARC (protease inhibitor)Efavirenz Bristol Myers Squibb HIV infection, (DMP 266, SUSTIVA ®) AIDS,ARC (−)6-Chloro-4-(S)- (non-nucleoside RT cyclopropylethynyl- inhibitor)4(S)-trifluoro- methyl-1,4-dihydro- 2H-3,1-benzoxazin- 2-one, StocrinEL10 Elan Corp, PLC HIV infection (Gainesville, GA) Etravirine Tibotec/J& J HIV infection, AIDS, ARC (non- nucleoside reverse transcriptaseinhibitor) Famciclovir SmithKline Herpes zoster, herpes simplex GS 840Gilead HIV infection, AIDS, ARC (reverse transcriptase inhibitor) HBY097Hoechst Marion HIV infection, Roussel AIDS, ARC (non-nucleoside reversetranscriptase inhibitor) Hypericin VIMRx Pharm HIV infection, AIDS, ARCRecombinant Human Triton Biosciences AIDS, Kaposi's Interferon Beta(Almeda, CA) sarcoma, ARC Interferon alfa-n3 Interferon Sciences ARC,AIDS Indinavir Merck HIV infection, AIDS, ARC, asymptomatic HIVpositive, also in combination with AZT/ddI/ddC ISIS 2922 ISISPharmaceuticals CMV retinitis KNI-272 Nat'l Cancer Institute HIV-assoc.diseases Lamivudine, 3TC GlaxoWellcome HIV infection, AIDS, ARC (reversetranscriptase inhibitor); also with AZT Lobucavir Bristol-Myers SquibbCMV infection Nelfinavir Agouron HIV infection, Pharmaceuticals AIDS,ARC (protease inhibitor) Nevirapine Boeheringer HIV infection, IngleheimAIDS, ARC (RT inhibitor) Novapren Novaferon Labs, Inc. HIV inhibitor(Akron, OH) Peptide T Peninsula Labs AIDS Octapeptide (Belmont, CA)Sequence Trisodium Astra Pharm. CMV retinitis, HIV PhosphonoformateProducts, Inc. infection, other CMV infections PNU-140690 PharmaciaUpjohn HIV infection, AIDS, ARC (protease inhibitor) Probucol Vyrex HIVinfection, AIDS RBC-CD4 Sheffield Med. HIV infection, Tech (Houston, TX)AIDS, ARC Ritonavir Abbott HIV infection, AIDS, ARC (protease inhibitor)Saquinavir Hoffmann-LaRoche HIV infection, AIDS, ARC (proteaseinhibitor) Stavudine; d4T Bristol-Myers Squibb HIV infection, AIDS,Didehydrodeoxy- ARC Thymidine Tipranavir Boehringer Ingelheim HIVinfection, AIDS, ARC (protease inhibitor) Valaciclovir GlaxoWellcomeGenital HSV & CMV infections VIRAZOLE ® Viratek/ICN Asymptomatic HIV(Ribavirin) (Costa Mesa, CA) positive, LAS, ARC VX-478 Vertex HIVinfection, AIDS, ARC Zalcitabine Hoffmann-LaRoche HIV infection, AIDS,ARC, with AZT Zidovudine; AZT GlaxoWellcome HIV infection, AIDS, ARC,Kaposi's sarcoma, in combination with other therapies Tenofovirdisoproxil, Gilead HIV infection, AIDS, fumarate salt (reversetranscriptase (VIREAD ®) inhibitor) EMTRIVA ® Gilead HIV infection,AIDS, (Emtricitabine) (FTC) (reverse transcriptase inhibitor) COMBAVIR ®GSK HIV infection, AIDS, (reverse transcriptase inhibitor) Abacavirsuccinate GSK HIV infection, AIDS, (or ZIAGEN ®) (reverse transcriptaseinhibitor) REYATAZ ® Bristol-Myers Squibb HIV infection (or atazanavir)AIDS, protease inhibitor FUZEON ® Roche/Trimeris HIV infection(enfuvirtide AIDs, viral fusion or T-20) inhibitor LEXIVA ® (orGSK/Vertex HIV infection, AIDS, viral fosamprenavir calcium) proteaseinhibitor Selzentry (maraviroc) Pfizer HIV infection, AIDS, (UK 427857)(CCR5 antagonist, in development) TRIZIVIR ® GSK HIV infection, AIDS,(three drug combination) Bevirimat Panacos HIV infection, AIDS,(maturation inhibitor, in development) Sch-417690 (vicriviroc)Schering-Plough HIV infection, AIDS, (CCR5 antagonist, in development)TAK-652 Takeda HIV infection, AIDS, (CCR5 antagonist, in development)GSK 873140 GSK/ONO HIV infection, AIDS, (ONO-4128) (CCR5 antagonist, indevelopment) Integrase Inhibitor Merck HIV infection, AIDS MK-0518Raltegravir TRUVADA ® Gilead Combination of Tenofovir disoproxilfumarate salt (VIREAD ®) and EMTRIVA ® (Emtricitabine) IntegraseInhibitor Gilead/Japan Tobacco HIV infection, AIDS, viral GS917/JTK-303integrase inhibitor in Elvitegravir development Triple drug Gilead/Combination of Tenofovir combination Bristol-Myers Squibb disoproxilfumarate salt Atripla (VIREAD ®), EMTRIVA ® (Emtricitabine), andSUSTIVA ® (Efavirenz) IMMUNOMODULATORS AS-101 Wyeth-Ayerst AIDSBropirimine Pharmacia Upjohn Advanced AIDS Acemannan Carrington Labs,Inc. AIDS, ARC (Irving, TX) CL246,738 Wyeth Lederle AIDS, Kaposi's Labssarcoma FP-21399 Fuki ImmunoPharm Blocks HIV fusion with CD4+ cellsGamma Interferon Genentech ARC, in combination w/TNF (tumor necrosisfactor) Granulocyte Genetics Institute AIDS Macrophage Colony SandozStimulating Factor Granulocyte Hoechst-Roussel AIDS Macrophage ColonyImmunex Stimulating Factor Granulocyte Schering-Plough AIDS, combinationMacrophage Colony with AZT Stimulating Factor HIV Core Particle RorerSeropositive HIV Immunostimulant IL-2 Cetus AIDS, in combinationInterleukin-2 with AZT IL-2 Hoffman-LaRoche AIDS, ARC, HIV, inInterleukin-2 Immunex combination with AZT IL-2 Chiron AIDS, increase inInterleukin-2 CD4 cell counts (aldeslukin) Immune Globulin CutterBiological Pediatric AIDS, in Intravenous (Berkeley, CA) combinationwith AZT (human) IMREG-1 Imreg AIDS, Kaposi's (New Orleans, LA) sarcoma,ARC, PGL IMREG-2 Imreg AIDS, Kaposi's (New Orleans, LA) sarcoma, ARC,PGL Imuthiol Diethyl Merieux Institute AIDS, ARC Dithio CarbamateAlpha-2 Schering Plough Kaposi's sarcoma Interferon with AZT, AIDSMethionine- TNI Pharmaceutical AIDS, ARC Enkephalin (Chicago, IL) MTP-PECiba-Geigy Corp. Kaposi's sarcoma Muramyl-Tripeptide Granulocyte AmgenAIDS, in combination Colony Stimulating with AZT Factor Remune ImmuneResponse Immunotherapeutic Corp. rCD4 Genentech AIDS, ARC RecombinantSoluble Human CD4 rCD4-IgG AIDS, ARC hybrids Recombinant Biogen AIDS,ARC Soluble Human CD4 Interferon Hoffman-La Roche Kaposi's sarcoma Alfa2a AIDS, ARC, in combination with AZT SK&F106528 SmithKline HIVinfection Soluble T4 Thymopentin Immunobiology HIV infection ResearchInstitute (Annandale, NJ) Tumor Necrosis Genentech ARC, in combinationFactor; TNF with gamma Interferon ANTI-INFECTIVES Clindamycin withPharmacia Upjohn PCP Primaquine Fluconazole Pfizer Cryptococcalmeningitis, candidiasis Pastille Squibb Corp. Prevention of NystatinPastille oral candidiasis Ornidyl Merrell Dow PCP EflornithinePentamidine LyphoMed PCP treatment Isethionate (IM & IV) (Rosemont, IL)Trimethoprim Antibacterial Trimethoprim/sulfa Antibacterial PiritreximBurroughs Wellcome PCP treatment Pentamidine Isethionate FisonsCorporation PCP prophylaxis for Inhalation Spiramycin Rhone-PoulencCryptosporidial diarrhea Intraconazole- Janssen-Pharm. Histoplasmosis;R51211 cryptococcal meningitis Trimetrexate Warner-Lambert PCPDaunorubicin NeXstar, Sequus Kaposi's sarcoma Recombinant Human OrthoPharm. Corp. Severe anemia Erythropoietin assocociated with AZT therapyRecombinant Human Serono AIDS-related Growth Hormone wasting, cachexiaMegestrol Acetate Bristol-Myers Squibb Treatment of anorexiaassocociated with AIDS Testosterone ALZA ®, SmithKline AIDS-relatedwasting Total Enteral Norwich Eaton Diarrhea and malabsorption NutritionPharmaceuticals related to AIDS

Additionally, the compounds of the disclosure herein set forth may beused in combination with other HIV entry inhibitors. Examples of suchHIV entry inhibitors are discussed in Drugs of the Future,24(12):1355-1362 (1999); Cell, 9:243-246 (Oct. 29, 1999); and DrugDiscovery Today, 5(5):183-194 (May 2000) and Meanwell, N. A. et al.,“Inhibitors of the entry of HIV into host cells”, Curr. Op. Drug Disc.Dev, 6(4):451-461 (2003). Specifically the compounds can be utilized incombination with other attachment inhibitors, fusion inhibitors, andchemokine receptor antagonists aimed at either the CCR5 or CXCR4coreceptor.

It will be understood that the scope of combinations of the compounds ofthis disclosure with AIDS antivirals, immunomodulators, anti-infectives,HIV entry inhibitors or vaccines is not limited to the list in the aboveTable but includes, in principle, any combination with anypharmaceutical composition useful for the treatment of AIDS.

Preferred combinations are simultaneous or alternating treatments with acompound of the present disclosure and an inhibitor of HIV proteaseand/or a non-nucleoside inhibitor of HIV reverse transcriptase. Anoptional fourth component in the combination is a nucleoside inhibitorof HIV reverse transcriptase, such as AZT, 3TC, ddC or ddI. A preferredinhibitor of HIV protease is REYATAZ® (active ingredient Atazanavir).Typically a dose of 300 to 600 mg is administered once a day. This maybe co-administered with a low dose of Ritonavir (50 to 500 mgs). Anotherpreferred inhibitor of HIV protease is KALETRA®. Another usefulinhibitor of HIV protease is indinavir, which is the sulfate salt ofN-(2(R)-hydroxy-1-(S)-indanyl)-2(R)-phenylmethyl-4-(S)-hydroxy-5-(1-(4-(3-pyridyl-methyl)-2(S)—N′-(t-butylcarboxamido)-piperazinyl))-pentaneamideethanolate, and is synthesized according to U.S. Pat. No. 5,413,999.Indinavir is generally administered at a dosage of 800 mg three times aday. Other preferred protease inhibitors are nelfinavir and ritonavir.Another preferred inhibitor of HIV protease is saquinavir which isadministered in a dosage of 600 or 1200 mg tid. Preferred non-nucleosideinhibitors of HIV reverse transcriptase include efavirenz. Thesecombinations may have unexpected effects on limiting the spread anddegree of infection of HIV. Preferred combinations include those withthe following (1) indinavir with efavirenz, and, optionally, AZT and/or3TC and/or ddI and/or ddC; (2) indinavir, and any of AZT and/or ddIand/or ddC and/or 3TC, in particular, indinavir and AZT and 3TC; (3)stavudine and 3TC and/or zidovudine; (4) zidovudine and lamivudine and141W94 and 1592U89; (5) zidovudine and lamivudine. (The preparation ofddC, ddI and AZT are also described in EP 0 484 071.)

In such combinations the compound of the present disclosure and otheractive agents may be administered separately or in conjunction. Inaddition, the administration of one element may be prior to, concurrentto, or subsequent to the administration of other agent(s).

General Chemistry (Methods of Synthesis)

The present invention comprises compounds of Formula I, theirpharmaceutical formulations, and their use in patients suffering from orsusceptible to HIV infection. The compounds of Formula I includepharmaceutically acceptable salts thereof. General procedures toconstruct compounds of Formula I and intermediates useful for theirsynthesis are described in the following Schemes (after theAbbreviations).

Abbreviations

One or more of the following abbreviations, most of which areconventional abbreviations well known to those skilled in the art, maybe used throughout the description of the disclosure and the examples:

-   h=hour(s)-   rt=room temperature-   mol=mole(s)-   mmol=millimole(s)-   g=gram(s)-   mg=milligram(s)-   mL=milliliter(s)-   TFA=trifluoroacetic Acid-   DCE=1,2-Dichloroethane-   CH₂Cl₂=dichloromethane-   TPAP=tetrapropylammonium perruthenate-   THF=tetrahydrofuran-   DEPBT=3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one-   DMAP=4-dimethylaminopyridine-   P-EDC=polymer supported    1-(3-dimethylaminopropyl)-3-ethylcarbodiimide-   EDC=1-(3-dimethylaminopropyl)-3-ethylcarbodiimide-   DMF=N,N-dimethylformamide-   Hunig's Base=N,N-diisopropylethylamine-   MCPBA=meta-chloroperbenzoic acid-   azaindole=1H-pyrrolo-pyridine-   4-azaindole=1H-pyrrolo[3,2-b]pyridine-   5-azaindole=1H-pyrrolo[3,2-c]pyridine-   6-azaindole=1H-pyrrolo[2,3-c]pyridine-   7-azaindole=1H-pyrrolo[2,3-b]pyridine-   PMB=4-methoxybenzyl-   DDQ=2,3-dichloro-5,6-dicyano-1,4-benzoquinone-   OTf=trifluoromethanesulfonoxy-   NMM=4-methylmorpholine-   PIP-COPh=1-benzoylpiperazine-   NaHMDS=sodium hexamethyldisilazide-   EDAC=1-(3-dimethylaminopropyl)-3-ethylcarbodiimide-   TMS=trimethylsilyl-   DCM=dichloromethane-   DCE=dichloroethane-   MeOH=methanol-   THF=tetrahydrofuran-   EtOAc=ethyl acetate-   LDA=lithium diisopropylamide-   TMP-Li=2,2,6,6-tetramethylpiperidinyl lithium-   DME=dimethoxyethane-   DIBALH=diisobutylaluminum hydride-   HOBT=1-hydroxybenzotriazole-   CBZ=benzyloxycarbonyl-   PCC=pyridinium chlorochromate-   TBTU=O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    tetrafluoroborate-   DEBPT=3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one-   BOP=benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate

Preparation of Compounds of Formula I, Chemistry Schemes

A general reaction scheme is set forth as follows:

For the preparation of substituent “A” above, the procedures set forthin U.S. Pat. Nos. 6,476,034, 6,573,262, 6,469,006 and 7,354,924, as wellas WO 2004/004337 are useful, and are incorporated herein by referencein their entirety.

Other specialized procedures are as follows:

When B=

for the preparation of the following compound:

the following reaction scheme may be useful:

In another embodiment, for the preparation of the following compounds:

the following schemes may be useful:

In another embodiment,

When B=

for the following compounds:

this reaction scheme may be useful:

In another embodiment, to prepare the following compounds

the following reaction schemes may be useful:

In another embodiment, for the preparation of the following compounds:

the following reaction may be useful:

In another embodiment, for the preparation of the following compounds:

the following reaction schemes may be useful:

In another embodiment, for the preparation of the following compounds

the following reaction scheme may be useful:

In another embodiment, for the preparation of the following compounds:

the following reaction scheme may be used:

In another embodiment,

When B=

for the following compound:

the following reaction scheme may be used:

In another embodiment, for the preparation of the following compounds:

the following reaction may be used:

In another embodiment,

When B=

for the preparation of the following compounds:

the following reaction scheme may be used:

In another embodiment,

When B=

for the preparation of the following compounds:

the following reaction schemes may be utilized:

In another embodiment,

When B=

for the preparation of the following compounds:

the following reaction scheme may be used:

EXAMPLES

The following examples illustrate typical syntheses of the compounds ofFormula I as described generally above. These examples are illustrativeonly and are not intended to limit the disclosure in any way. Thereagents and starting materials are readily available to one of ordinaryskill in the art.

Chemistry

Typical Procedures and Characterization of Selected Examples:

Unless otherwise stated, solvents and reagents were used directly asobtained from commercial sources, and reactions were performed under anitrogen atmosphere. Flash chromatography was conducted on Silica gel 60(0.040-0.063 particle size; EM Science supply). ¹H NMR spectra wererecorded on Bruker DRX-500f at 500 MHz (or Bruker DPX-300B or VarianGemini 300 at 300 MHz as stated). The chemical shifts were reported inppm on the 6 scale relative to δTMS=0. The following internal referenceswere used for the residual protons in the following solvents: CDCl₃(δ_(H) 7.26), CD₃OD (δ_(H) 3.30), and DMSO-d₆ (δ_(H) 2.50). Standardacronyms were employed to describe the multiplicity patterns: s(singlet), d (doublet), t (triplet), q (quartet), m (multiplet), b(broad), app (apparent). The coupling constant (J) is in Hertz. AllLiquid Chromatography (LC) data were recorded on a Shimadzu LC-10ASliquid chromatograph using a SPD-10AV UV-Vis detector with MassSpectrometry (MS) data determined using a MICROMASS® Platform for LC inelectrospray mode.

LC/MS Methods (i.e., Compound Identification)

Method 1:

-   Start % B=0, Final % B=100 over 3 minute gradient (1 minutes    collected after run)-   Flow Rate=4 mL/Min-   Solvent A=5% ACN-95% H₂O-10 mm Ammonium Acetate-   Solvent B=95% ACN-5% H₂O-10 mm Ammonium Acetate-   Column: PHENOMENEX® Luna 4.6×50 mm S10    Method 2:-   Start % B=0, Final % B=100 over 3 minute gradient (1 minutes    collected after run)-   Flow Rate=4 mL/Min-   Solvent A=10% MeOH-90% H₂O-0.1% TFA-   Solvent B=90% MeOH-10% H₂O-0.1% TFA-   Column: PHENOMENEX® Luna 10u C18 3.0×50 mm    Method 3:-   Start % B=0, Final % B=100 over 3 minute gradient (1 minutes    collected after run)-   Flow Rate=4 mL/Min-   Solvent A=90% H₂O-10% ACN-0.1% TFA-   Solvent B=10% H₂O-90% ACN-0.1% TFA-   Column: SunFire C18 5u 4.6×50 mm    Method 4:-   Start % B=0, Final % B=100 over 2 minute gradient (1 minutes    collected after run)-   Flow Rate=4 mL/Min-   Solvent A=90% H₂O-10% ACN-0.1% TFA-   Solvent B=10% H₂O-90% ACN-0.1% TFA-   Column: PHENOMENEX® Luna 4.6×50 mm S10    Method 5:-   Start % B=0, Final % B=100 over 2 minute gradient (1 minutes    collected after run)-   Wavelength=220-   Flow Rate=4 mL/min-   Solvent A=90% H₂O-10% MeOH-0.1% TFA-   Solvent B=10% H₂O-90% MeOH-0.1% TFA-   Column: PHENOMENEX® LUNA 4.6×30 mm S10    Method 6:-   Start % B=0, Final % B=100 over 2 minute gradient (1 minutes    collected after run)-   Wavelength=220-   Flow Rate=4 mL/min-   Solvent A=5% ACN-95% H₂O-10 mm Ammonium Acetate-   Solvent B=95% ACN-5% H₂O-10 mm Ammonium Acetate-   Column: PHENOMENEX® LUNA 4.6×30 mm S10    Method 7:-   Start % B=0, Final % B=100 over 2 minute gradient (1 minutes    collected after run)-   Flow Rate=5 mL/Min-   Solvent A=5% ACN-95% H₂O-10 mm Ammonium Acetate-   Solvent B=95% ACN-5% H₂O-10 mm Ammonium Acetate-   Column: PHENOMENEX® 5u C18 4.6×30 mm S10    Method 8:-   Start % B=0, Final % B=100 over 3 minute gradient (1 minutes    collected after run)-   Flow Rate=4 mL/Min-   Solvent A=10% MeOH-90% H₂O-0.1% TFA-   Solvent B=90% MeOH-10% H₂O-0.1% TFA-   Column: PHENOMENEX® Luna 4.6×50 mm S10    Method 9:-   Start % B=0, Final % B=100 over 2 minute gradient (1 minutes    collected after run)-   Flow Rate=4 mL/Min-   Solvent A=90% H₂O-10% MeOH-0.1% TFA-   Solvent B=10% H₂O-90% MeOH-0.1% TFA-   Column: PHENOMENEX® LUNA 4.6×50 mm S10    Method 10:-   Start % B=0, Final % B=100 over 2 minute gradient (1 minutes    collected after run)-   Wavelength=220-   Flow Rate=4 mL/min-   Solvent A=5% H₂O-95% MeOH-0.1% TFA-   Solvent B=95% H₂O-5% MeOH-0.1% TFA-   Column: PHENOMENEX® LUNA 3.0×50 mm S10    Method 11:-   Start % B=0, Final % B=30 over 2 minute gradient (1 minutes    collected after run)-   Wavelength=220-   Flow Rate=4 mL/min-   Solvent A=90% H₂O-10% MeOH-0.1% TFA-   Solvent B=10% H₂O-90% MeOH-0.1% TFA-   Column: PHENOMENEX® LUNA 4.6×30 mm S10    Method 12:-   Start % B=0, Final % B=50 over 2 minute gradient (1 minutes    collected after run)-   Wavelength=220-   Flow Rate=4 mL/min-   Solvent A=90% H₂O-10% MeOH-0.1% TFA-   Solvent B=10% H₂O-90% MeOH-0.1% TFA-   Column: PHENOMENEX® LUNA 4.6×30 mm S10

Compounds purified by preparative HPLC were diluted in methanol (1.2 ml)and purified using the following methods on a Shimadzu LC-10A automatedpreparative HPLC system.

Preparative HPLC Method (i.e., Compound Purification)

Purification Method: Initial gradient (40% B, 60% A) ramp to finalgradient (100% B, 0% A) over 20 minutes, hold for 3 minutes (100% B, 0%A)

-   Solvent A: 10% MeOH/90% H₂O/0.1% Trifluoroacetic Acid-   Solvent B: 10% H₂O/90% MeOH/0.1% Trifluoroacetic Acid-   Column: YMC C18 S5 20×100 mm column-   Detector Wavelength: 220 nm

Example A Preparation of Compound A of Formula 1

Process for the Preparation of Compound A-In-2:

This compound was prepared by the method described by Bryant, H. J. etal., in WO 01/44250.

To a stirred and cold (ice-bath cooling) suspension of benzyl3-oxopiperazine-1-carboxylate (A-In-1) (1.00 g) and K₂CO₃ (11.8 g) inCH₂Cl₂ (40 mL) was added under N₂ trimethyloxonium tetrafluoroborate(2.20 g, from Aldrich) in one portion. The cooling bath was removed andthe mixture was stirred at room temperature under N₂ for 19 h. Thismixture was poured into water (40 mL) under ice-cooling and the organicphase was collected. The aqueous phase was extracted with CH₂Cl₂. Thecombined CH₂Cl₂ phases were washed with water (20 mL), then with brine,dried (Na₂SO₄) and concentrated. The crude residual oil was purified bysilica gel column chromatography (5% MeOH/CH₂Cl₂) to give the titlecompound A-In-2 as colorless oil.

Process for the Preparation of Compound A-In-3 from A1-In-2:

A mixture of A1-In-2 (248 mg) and benzoic acid hydrazide (136 mg) intoluene (25 mL) was heated at reflux with a Dean-Stark trap for 24 h.After cooling, the mixture was concentrated in vacuo, and the residuewas purified by silica gel column chromatography (5% MeOH/CH₂Cl₂),followed by crystallization from Et₂O gave the title compound A-In-3 aswhite crystals.

Process for the Preparation of Compound A-In-4 from A-In-3:

A mixture of A1-In-3 in 30% HBr in HOAc (1.7 mL) was stirred at roomtemperature for 3 h. Concentration under vacuum provided an aqueoussolution which was extracted with CH₂Cl₂ (15 mL). The organic layer waswashed with saturated aqueous NaHCO₃, dried (Na₂SO₄) and concentrated.The residue was purified by silica gel column chromatography (10% of 10%c-NH₄OH/MeOH in CH₂Cl₂) to give A-In-4 as white solid.

Process for the Preparation of Compound A1 from A-In-4:

To a stirred solution of A-In-4 (30 mg) and A-In-S (40 mg) in CH₂Cl₂ (2mL) under N₂ was injected diisopropylethylamine (31 μL) and the mixturewas stirred for 1 h. After removal of solvents under vacuum, the residuewas purified by silica gel column chromatography (10% MeOH/CH₂Cl₂),followed by trituration from Et₂O to provide the title compound A1 asoff-white crystalline powder.

Characterization of A-In and A (Table A):

TABLE A Compound MS (M + H)⁺ MS (M + H)⁺ Observ. and No. StructureCalcd. Retention Time and NMR A-In-2

249 249. ¹H-NMR (CDCl₃, 500 MHz): δ ppm 3.46-3.49(2H, m), 3.56 (2H, m),3.74(3H, br.s), 3.99 (2H, br.s), 5.15(2H, s), 7.33- 7.38(5H, m). A-In-3

335 335. ¹H-NMR (CDCl₃): δppm 3.87 (2H, br.s), 4.08(2H, br.s), 4.95 (2H,s), 5.18(2H, s), 7.35(5H, s), 7.46(3H, br.s), 7.63(2H, br). ¹³C-NMR(CDCl₃): δppm 41.0, 41.7, 44.0, 68.2, 126.5, 128.2, 128.6, 128.8, 129.2,130.3, 135.9, 148.3, 153.4, 155.0. A-in-4

201 201. ¹H-NMR (CDCl₃): δppm 2.37 (1H, br.s), 3.17(2H, t, J = 5.5 Hz),4.00(2H, t, J = 5.5 Hz), 4.20(2H, s), 7.38-7.48(3H, m), 7.63(2H, dd, J =6.6, 2.9 Hz). A1

390 390. ¹H-NMR (300 MHz, DMSO- d₆): δppm 3.81(1.5H, t, J = 5 Hz),4.05-4.09(0.5H, m), 4.12 (1.5H, t, J = 5 Hz), 4.32 (0.5H, t, J = 5 Hz),4.84(0.5H, s), 5.03(1.5H, s), 7.03(1H, m), 7.24-7.34(1H, m), 7.37,7.40(1H, 2s, 3:1), 7.49-7.60 (3H, m), 7.68-7.76(2H, m), 8.29(0.25H, d, J= 3 Hz), 8.43 (0.75H, d, J = 2 Hz), 12.68 (1H, br.s).

Example B Preparation of Compounds B of Formula 1

General Process for the Preparation of Compound B from3-Phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine:

2-Keto acid (1 eq.),3-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine (1-5 eq.),coupling agent (TBTU, DEPBT or BOP) (1-5 eq.) and Hunig's Base (1-100eq.) were combined in DMF or THF. The mixture was stirred at roomtemperature for 17 hours. DMF or THF was removed via evaporation atreduced pressure and the residue was partitioned between ethyl acetateand 5-10% Na₂CO₃ or 5% NaHCO₃ or NH₄Cl aqueous solution. The aqueouslayer was extracted with ethyl acetate or methylene chloride. Theorganic phase combined and dried over anhydrous MgSO₄. Concentration invacuo provided a crude product, which was purified by trituration, orrecrystallization, or silica gel column chromatography, or Shimadzuautomated preparative HPLC system.

Characterization of B-In and B (Table B):

TABLE B Compound MS (M + H)⁺ MS (M + H)⁺ Observ. and No. StructureCalcd. Retention Time and NMR B1

484 484, Rf = 1.36 min (Method 5). ¹H NMR (500 MHz, MeOD): δppm 9.10(s,1H), 8.30-8.32 (m, 1 H), 7.75(s, 1H), 7.63- 7.68(m, 2H), 7.51-7.56(m,3H), 5.02-5.20(m, 2H), 3.93- 4.32(m, 7H), 2.53(s, 3H). B2

470 470, Rf = 1.40 min (Method 5). ¹H NMR (500 MHz, DMSO- d₆): δppm12.84(s, 1H), 8.93 (s, 1H), 8.29-8.40(m, 1H), 8.05-8.10(m, 1H), 7.93-8.00(m, 1H), 7.71-7.81(m, 2H), 7.50-7.58(m, 3H), 4.87- 5.10(m, 2H),3.85-4.33(m, 7H). B3

458 458, Rf = 1.53 min (Method 5). ¹H NMR (500 MHz, DMSO- d₆): δppm13.10(s, 1H), 9.01 (s, 1H), 8.41-8.62(m, 1H), 8.29-8.33(m, 1H), 8.07-8.15(m, 1H), 7.70-7.80(m, 2H), 7.49-7.58(m, 3H), 4.91- 5.09(m, 2H),4.13-4.34(m, 2H), 3.85-4.12(m, 2H). B4

514 514, Rf = 1.41 min (Method 1). ¹H NMR (500 MHz, MeOD): δppm 9.25(s,1H), 8.33-8.40 (m, 1H), 7.81-7.85(m, 1H), 7.66-7.74(m, 2H), 7.53-7.60(m, 3H), 5.02-5.24(m, 2H), 4.70(s, 2H), 3.93-4.37 (m, 7H), 3.52(s,3H).

Example C Preparation of Compounds C of Formula 1

General Process for the Preparation of Compound C-In-1 from3-Bromo-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine:

2-Keto acid (1 eq.),3-bromo-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine (1-5 eq.),coupling agent (TBTU, DEPBT or BOP) (1-5 eq.) and Hunig's Base (1-100eq.) were combined in DMF or THF. The mixture was stirred at roomtemperature for 17 hours. DMF or THF was removed via evaporation atreduced pressure and the residue was partitioned between ethyl acetateand 5-10% Na₂CO₃ or 5% NaHCO₃ or NH₄Cl aqueous solution. The aqueouslayer was extracted with ethyl acetate or methylene chloride. Theorganic phase combined and dried over anhydrous MgSO₄. Concentration invacuo provided a crude product, which was purified by trituration, orrecrystallization, or silica gel column chromatography, or Shimadzuautomated preparative HPLC system, to afford C-In-1.

General Process for the Preparation of Compound C from C-In-1:

C-In-1 (1 eq.), boronic or stannane agent (1-10 eq.) and palladiumcatalyst (e.g., tetrakis(triphenylphosphine)palladium,bis(diphenylphosphino)ferrocene palladium (II) chloride,bis(triphenylphosphine)palladium(II) chloride) (0.05-1 eq.)

with or without base (e.g., Cs₂CO₃, K₂CO₃, NaCO₃, Na₃PO₄, NaH₂PO₄,Na₂HPO₄, Et₃N, iPr₂NEt, t-BuOK, t-BuONa) were combined in DMF ordioxane, with or without water. The reaction was either heated to 100°C. to 200° C. in sealed tube or carried out in the microwave synthesizerfor 20 minutes to 72 hours. The mixture was diluted with MeOH andfiltered. The filtration was concentrated and purified by trituration,or recrystallization, or silica gel column chromatography, or Shimadzuautomated preparative HPLC system, to afford Compound C.

Characterization of C-In and C (Table C):

TABLE C MS (M + H)⁺ Observ. Compound MS (M + H)⁺ and Retention Time No.Structure Calcd. and NMR C-In-1

486 486, Rf = 1.35 min (Method 9). C1

498 498, Rf = 1.45 min (Method 5). ¹H NMR (500 MHz, MeOD): δppm 9.12-9.18(m, 1H), 8.34(s, 1H), 7.78-7.84(m, 1H), 7.31-7.47(m, 4H),5.01-5.25(m, 2H), 3.98-4.23(m, 4H), 3.92-3.95(m, 3H), 2.50-2.58(m, 3H),2.25-2.32(m, 3H). C2

502 502, Rf = 1.40 min (Method 5). ¹H NMR (500 MHz, MeOD): δppm 9.15(s,1H), 8.31-8.39(m, 1H), 7.76-7.83(m, 1H), 7.23-7.62(m, 4H), 5.00-5.26(m,2H), 3.98-4.23(m, 4H), 3.84-3.98(m, 3H), 2.54(s, 3H). C3

485 485, Rf = 1.12 min (Method 6). C4

527 527, Rf = 1.70 min (Method 8). C5

514 514, Rf = 1.44 min (Method 1). C6

518 518, Rf = 1.52 min (Method 1). C7

498 (M − H) 498 (M − H)⁺, Rf = 1.36 min (Method 1). C8

498 498.

Example D Preparation of Compounds D of Formula 1

General Process for the Preparation of Compound D from D-In-1:

2-Keto acid (1 eq.), D-In-1 (1-5 eq.), coupling agent (TBTU, DEPBT orBOP) (1-5 eq.) and Hunig's Base (1-100 eq.) were combined in DMF or THF.The mixture was stirred at room temperature for 17 hours. DMF or THF wasremoved via evaporation at reduced pressure and the residue waspartitioned between ethyl acetate and 5-10% Na₂CO₃ or 5% NaHCO₃ or NH₄Claqueous solution. The aqueous layer was extracted with ethyl acetate ormethylene chloride. The organic phase combined and dried over anhydrousMgSO₄. Concentration in vacuo provided a crude product, which waspurified by trituration, or recrystallization, or silica gel columnchromatography, or Shimadzu automated preparative HPLC system.

Characterization of D (Table D):

TABLE D Compound MS (M + H)⁺ MS (M + H)⁺ Observ. and No. StructureCalcd. Retention Time and NMR D1

483 483, Rf = 1.32 min (Method 5). ¹H NMR (500 MHz, CDCl₃) δppm11.07-11.13(m, 1H), 9.08(s, 1H), 8.22-8.27(m, 1H), 7.34-7.45(m, 5H),7.10- 7.17(m, 1H), 4.93-5.10(m, 2H), 3.94-4.15(m, 4H), 3.85- 3.91(m,3H), 2.55(s, 3H). D2

469 469, Rf = 1.31 min (Method 5). ¹H NMR (500 MHz, MeOD): δppm 8.74(s,1H), 8.31-8.39 (m, 1H), 7.89(s, 1H), 7.83(s, 1H), 7.34-7.44(m, 5H),7.03- 7.08(m, 1H), 4.87-5.05(m, 2H), 3.89-4.20(m, 7H). D3

480 480, Rf = 1.00 min (Method 5). ¹H NMR (500 MHz, MeOD): δppm9.27-9.32(m, 1H), 9.15- 9.21(m, 2H), 8.43-8.49(m, 1H), 8.18(s, 1H),7.49-7.58 (m, 6H), 5.19-5.32(m, 2H), 4.06-4.34(m, 7H).

Example E Preparation of Compounds E of Formula 1

General Process for the Preparation of Compound E-In-2 from E-In-1:

A round bottom flask was charged with E-In-1 (1 eq.), CH₂Cl₂, mesityleneand Tin(IV) chloride (0.3 eq.). The mixture was brought to reflux thenaminoacetaldehyde diethyl acetal (2 eq.) was added slowly. The reactionwas refluxed for 2-3d. The reaction was diluted with CH₂Cl₂ and filteredthrough activated charcoal and the filtrate was evaporated giving asolid which was purified by trituration, or recrystallization, or silicagel column chromatography, or Shimadzu automated preparative HPLCsystem, to afford E-In-2.

General Process for the Preparation of Compound E-In-3 from E-In-2:

A round bottom flask was charged with E-In-2 (1 eq.), CCl₄ andN-bromosuccinimide (1 eq.). The solution was refluxed for 30 minutesthen allowed to cool. The CCl₄ solution was decanted off a brown solidand evaporated. The residue was purified by trituration, orrecrystallization, or silica gel column chromatography, or Shimadzuautomated preparative HPLC system, to afford E-In-3.

General Process for the Preparation of Compound E-In-4 from E-In-3:

E-In-3 (1 eq.), boronic or stannane agent (1-10 eq.) and palladiumcatalyst (e.g., tetrakis(triphenylphosphine)palladium,bis(diphenylphosphino)ferrocene palladium (II) chloride,bis(triphenylphosphine)palladium(II) chloride) (0.05-1 eq.) with orwithout base (e.g., Cs₂CO₃, K₂CO₃, NaCO₃, Na₃PO₄, NaH₂PO₄, Na₂HPO₄,Et₃N, iPr₂NEt, t-BuOK, t-BuONa) were combined in DMF or dioxane, with orwithout water. The reaction was either heated to 100° C. to 200° C. insealed tube or carried out in the microwave synthesizer for 20 minutesto 72 hours. The mixture was diluted with MeOH and filtered. Thefiltration was concentrated and purified by HPLC or recrystallization tooffer Compound E-In-4.

General Process for the Preparation of Compound E-In-5 from E-In-4:

E-In-4 was added into a solution TFA in dichloromethane (1% to 100%) orHCl in ether (2N). The reaction mixture was stirred at room temperaturefor 30 minutes to 18 hours. Concentration under vacuum provided aresidue which was purified by silica chromatography or HPLC to affordE-In-5.

General Process for the Preparation of Compound E from E-In-5:

2-Keto acid (1 eq.), E-In-5 (1-5 eq.), coupling agent (TBTU, DEPBT orBOP) (1-5 eq.) and Hunig's Base (1-100 eq.) were combined in DMF or THF.The mixture was stirred at room temperature for 17 hours. DMF or THF wasremoved via evaporation at reduced pressure and the residue waspartitioned between ethyl acetate and 5-10% Na₂CO₃ or 5% NaHCO₃ or NH₄Claqueous solution. The aqueous layer was extracted with ethyl acetate ormethylene chloride. The organic phase combined and dried over anhydrousMgSO₄. Concentration in vacuo provided a crude product, which waspurified by trituration, or recrystallization, or silica gel columnchromatography, or Shimadzu automated preparative HPLC system.

Characterization of E-In and E (Table E):

TABLE E Compound MS (M + H)⁺ MS (M + H)⁺ Observ. and No. StructureCalcd. Retention Time and NMR E-In-2

224 224. ¹H NMR (DMSO-d₆): δ1.46 (s, 9H), 3.82-3.84(m, 2H), 3.97-3.99(m,2H), 4.68(s, 2H), 6.85(s, 1H), 7.04(s, 1H). E-In-3

302 302. ¹H NMR (DMSO-d₆): δ1.46 (s, 9H), 3.85(s, 4H), 4.65(s, 2H),6.99(s, 1H). E-In-4

301 301. ¹H NMR (DMSO-d₆) δ1.47 (s, 9H), 3.82-3.84(t, 2H, J = 5 Hz),4.51-4.53(t, 2H, J = 5 Hz), 4.78(s, 2H), 7.11-7.13 (dd, 1H, J = 7.5 Hz),7.43(s, 1H), 7.51-7.53(d, 1H, J = 8 Hz), 7.64-7.68(dd, 1H, J = 8, 2 Hz),8.53-8.54(d, 1H, J = 5 Hz). E-In-5

201 201. E1

484 484. ¹H NMR (DMSO-d₆): δ2.52 (s, 3H), 3.85 & 3.93(s, 3H), 3.97-3.99& 4.16-4.18(t, 2H, J = 5 Hz), 4.51-4.53 & 4.67-4.69(t, 2H, J = 5 Hz),5.10-& 4.93(s, 2H), 7.37- 7.42(m, 1H), 7.86-7.95(m, 3H), 8.07(s, 1H),8.40-8.41 & 8.32-8.33(d, 1H, J = 3 Hz), 8.61-8.61 & 8.68- 8.69(d, 1H, J= 3 Hz), 9.25(s, 1H), 12.51 & 12.46(s, 1H).

Example F Preparation of Compounds F of Formula 1

General Process for the Preparation of Compound F-In-1 from3-Bromo-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine:

2-Keto acid (1 eq.), 3-bromo-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine(1-5 eq.), coupling agent (TBTU, DEPBT or BOP) (1-5 eq.) and Hunig'sBase (1-100 eq.) were combined in DMF or THF. The mixture was stirred atroom temperature for 17 hours. DMF or THF was removed via evaporation atreduced pressure and the residue was partitioned between ethyl acetateand 5-10% Na₂CO₃ or 5% NaHCO₃ or NH₄Cl aqueous solution. The aqueouslayer was extracted with ethyl acetate or methylene chloride. Theorganic phase combined and dried over anhydrous MgSO₄. Concentration invacuo provided a crude product, which was purified by trituration, orrecrystallization, or silica gel column chromatography, or Shimadzuautomated preparative HPLC system.

General Process for the Preparation of Compound F from F-In-1:

F-In-1 (1 eq.), boronic or stannane agent (1-10 eq.) and palladiumcatalyst (e.g., tetrakis(triphenylphosphine)palladium,bis(diphenylphosphino)ferrocene palladium (II) chloride,bis(triphenylphosphine)palladium(II) chloride) (0.05-1 eq.) with orwithout base (e.g., Cs₂CO₃, K₂CO₃, NaCO₃, Na₃PO₄, NaH₂PO₄, Na₂HPO₄,Et₃N, iPr₂NEt, t-BuOK, t-BuONa) were combined in DMF or dioxane, with orwithout water. The reaction was either heated to 100° C. to 200° C. insealed tube or carried out in the microwave synthesizer for 20 minutesto 72 hours. The mixture was diluted with MeOH and filtered. Thefiltration was concentrated and purified by HPLC or recrystallization tooffer Compound F.

Characterization of F-In and F (Table F):

TABLE F Compound MS (M + H)⁺ MS (M + H)⁺ Observ. and No. StructureCalcd. Retention Time and NMR F-In-1

485 485, Rf = 1.26 min (Method 9). F1

499 499, Rf = 1.32 min (Method 9). F2

484 484, Rf = 1.11 min (Method 9). F3

499 499, Rf = 1.27 min (Method 9). F4

514 514, Rf = 1.48 min (Method 1). F5

508 508, Rf = 1.52 min (Method 1). F6

484 484, Rf = 1.33 min (Method 8).

Example G Preparation of Compounds G of Formula 1

General Process for the Preparation of Compound G-In-1 from E-In-4:

A round bottom flask was charged with acetonitrile, 2-propanol, E-In-4(1 eq.) and N-chlorosuccinimide or N-bromosuccinimide (1.05 eq.). Thereaction was refluxed under nitrogen for 0.25 h. The reaction wasdiluted with ether, washed with water then brine, dried over MgSO₄ andevaporated giving a creamy white powder which was purified bytrituration, or recrystallization, or silica gel column chromatography,or Shimadzu automated preparative HPLC system.

General Process for the Preparation of Compound G-In-2 from G-In-1:

G-In-1 was added into a solution TFA in dichloromethane (1% to 100%) orHCl in ether (2N). The reaction mixture was stirred at room temperaturefor 30 minutes to 18 hours. Concentration under vacuum provided aresidue which was purified by silica chromatography or HPLC to affordG-In-2.

General Process for the Preparation of Compound G from G-In-2:

2-Keto acid (1 eq.), G-In-2 (1-5 eq.), coupling agent (TBTU, DEPBT orBOP) (1-5 eq.) and Hunig's Base (1-100 eq.) were combined in DMF or THF.The mixture was stirred at room temperature for 17 hours. DMF or THF wasremoved via evaporation at reduced pressure and the residue waspartitioned between ethyl acetate and 5-10% Na₂CO₃ or 5% NaHCO₃ or NH₄Claqueous solution. The aqueous layer was extracted with ethyl acetate ormethylene chloride. The organic phase combined and dried over anhydrousMgSO₄. Concentration in vacuo provided a crude product, which waspurified by trituration, or recrystallization, or silica gel columnchromatography, or Shimadzu automated preparative HPLC system.

Characterization of G-In and G (Table G):

TABLE G Compound MS (M + H)⁺ MS (M + H)⁺ Observ. and No. StructureCalcd. Retention Time and NMR G-In-1a

334 334. ¹H NMR (DMSO-d₆): δ1.49 (s, 9H), 3.78-3.80(m, 2H), 3.86-3.88(m,2H), 4.71(s, 2H), 7.38-7.40(m, 3H), 7.44-7.47(m, 2H). G-In-1b

378 ¹H NMR (DMSO-d₆): δ1.48 (s, 9H), 3.79-3.80(m, 2H), 3.86-3.88(m, 2H),4.79(s, 2H), 7.38-7.48(m, 5H). G1

517 517. ¹H NMR (DMSO-d₆): δ3.17 (s, 3H), 3.18(s, 3H), 3.89- 3.91(q,2H), 4.08-4.11(q, 2H), 4.89 & 4.72(s, 2H), 7.43-7.55(m, 5H), 7.89 &7.90(s, 1H), 8.36 & 8.32(s, 1H), 9.25(s, 1H), 12.47(s, 1H). G2

561 561. ¹H NMR (DMSO-d₆): δ2.52 (s, 3H), 3.83 & 3.94(s, 3H), 3.50-3.90& 4.05-4.09 (m, 2H), 4.90 & 4.72(s, 2H), 7.42-7.55(m, 5H), 7.89 &7.90(s, 1H), 83.6 & 8.32(s, 1H), 9.25(s, 1H), 12.47(s, 1H).

Example H Preparation of Compounds H of Formula 1

General Process for the Preparation of Compound H-In-2 from H-In-1:

Copper or CuBr or CuCl or CuI was added in the mixture of H-In-1 andsodium methoxide in methanol solution (0.5-4N) in a sealed tube. Thereaction mixture was heated to 100-150° C. for 30 minutes to 18 hours.1N HCl was then added to adjust pH value to 7. The solution wasextracted with EtOAc or Ether or dichloromethane. The combined organiclayer was washed with brine and then dried over MgSO₄. Concentrationunder vacuum provided a residue which was purified by silicachromatography or HPLC to afford H-In-2.

General Process for the Preparation of Compound H-In-4 from H-In-1:

[1,3-Bis(diphenylphosphino)nickel(II) chloride was added in the mixtureof H-In-1 and 2N trimethylalumnium in toluene in a sealed tube. Thereaction mixture was heated to 100-150° C. for 30 minutes to 18 hours.1N HCl was then added to adjust pH value to 7. The solution wasextracted with EtOAc or Ether or dichloromethane. The combined organiclayer was washed with brine and then dried over MgSO₄. Concentrationunder vacuum provided a residue which was purified by silicachromatography or HPLC to afford H-In-4.

General Process for the Preparation of Compound H-In-3 or H-In-5 fromH-In-2 or H-In-4:

H-In-2 or H-In-4 was added into a solution TFA in dichloromethane (1% to100%) or HCl in ether (2N). The reaction mixture was stirred at roomtemperature for 30 minutes to 18 hours. Concentration under vacuumprovided a residue which was purified by silica chromatography or HPLCto afford H-In-3 or H-In-5.

General Process for the Preparation of Compound H from H-In-3 or H-In-5:

2-Keto acid (1 eq.), H-In-3 or H-In-5 (1-5 eq.), coupling agent (TBTU,DEPBT or BOP) (1-5 eq.) and Hunig's Base (1-100 eq.) were combined inDMF or THF. The mixture was stirred at room temperature for 17 hours.DMF or THF was removed via evaporation at reduced pressure and theresidue was partitioned between ethyl acetate and 5-10% Na₂CO₃ or 5%NaHCO₃ or NH₄Cl aqueous solution. The aqueous layer was extracted withethyl acetate or methylene chloride. The organic phase combined anddried over anhydrous MgSO₄. Concentration in vacuo provided a crudeproduct, which was purified by trituration, or recrystallization, orsilica gel column chromatography, or Shimadzu automated preparative HPLCsystem.

Characterization of H-In and H (Table H):

TABLE H Compound MS (M + H)⁺ MS (M + H)⁺ Observ. and No. StructureCalcd. Retention Time and NMR H-In-2b

331 331, Rf = 2.16 min (Method 1). H-In-3a

230 230. H-In-3b

231 231, Rf = 1.38 min (Method 1). H-In-5a

215 215, Rf = 0.48 min (Method 9). H1a

HRMS: 513.1993 HRMS: 513.1992. ¹H NMR (DMSO-d₆): δ2.50(s, 3H), 3.81 &3.78 (s, 3H), 3.86 & 3.92(s, 3H), 3.87-3.89 & 4.08- 4.10(t, 2H, J = 5Hz), 3.97- 3.99 & 4.14-4.16(t, 2H, J = 5 Hz), 4.86 & 4.67 (s, 2H),7.42-7.55(m, 5H), 7.89 & 7.90(s, 1H), 8.36 & 8.32(s, 1H), 9.25 (s, 1H),12.47(s, 1H). H1b

514 514, Rf = 1.68 min (Method 1). H2

498 498, Rf = 1.71 min (Method 8).

Example I Preparation of Compounds I of Formula 1

Process for the Preparation of Compound I-In-1 from Pyrazin-2-amine

3-Bromo-1,1,1-trifluoroacetone (1 eq.) was added to a solution ofpyrazin-2-amine (1 eq.) in dioxane and the mixture was heated at 40-110°C. for 20 h. The solid formed was collected by filtration and washedtwice with EtOAc. This solid was heated in isopropanol at reflux for 3hours. Reaction mixture cooled to room temperature and partitionedbetween ethyl acetate and saturated aqueous sodium bicarbonate. Theaqueous phase was extracted once more with ethyl acetate. The combinedorganic layers were washed with brine, dried over sodium sulfate,filtered and concentrated in vacuo to afford a solid containing2-(trifluoromethyl)imidazo[1,2-a]pyrazine, 1-In-1. This material couldbe purified by trituration, or recrystallization, or silica gel columnchromatography, or Shimadzu automated preparative HPLC system, or usedas is without further purification.

Process for the Preparation of Compound I-In-2 from 1-In-1:

The crude material containing 2-(trifluoromethyl)imidazo[1,2-a]pyrazine,1-In-1 was dissolved in MeOH and was treated with Pd/C and hydrogen at 1atm of pressure. The mixture was stirred at room temperature for 2 h.Reaction transferred to a Parr shaker reactor and kept under 50 psi for20 h. Solution filtered through CELITE® to remove catalyst andconcentrated in vacuo. Residue containing2-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine, 1-In-2,could be purified by trituration, or recrystallization, or silica gelcolumn chromatography, or Shimadzu automated preparative HPLC system, orused as is without further purification.

Process for the Preparation of Compound I-In-3 from 1-In-2:

The solution of2-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (1 eq.),Hunig's Base (1-20 eq.) and BOC₂O (1-5 eq.) was stirred in CH₂Cl₂ atroom temperature for 1-20 h. The volume was reduced to half in vacuo andthen the solution was partitioned between ethyl acetate and 0.5N HCl.Aqueous phase was extracted twice with EtOAc. The combined organicphases were dried over sodium sulfate, filtered and concentrated invacuo. The residue was purified on silica gel to afford 1-In-3.

Process for the Preparation of Compound I-In-4 from 1-In-3:

1-In-3 (1 eq.) in chloroform was cooled to 0° C. and bromine (1 eq.) wasadded slowly. The reaction was stirred at this temperature for 30 minand then placed at room temperature for 1.5 h. Bromine (1 eq.) was addedand the stirring continued for 2 h. The reaction was quenched with aq.sat. NaHCO₃, extracted with AcOEt, dried over Na₂SO₄, and purified onsilica gel (hexanes-10% EtOAc/Hex) to afford I-In-4.

General Process for the Preparation of Compound I-In-5 from 1-In-4:

1-In-4 (1 eq.), boronic or stannane agent (1-10 eq.) and palladiumcatalyst (e.g., tetrakis(triphenylphosphine)palladium,bis(diphenylphosphino)ferrocene palladium (II) chloride,bis(triphenylphosphine)palladium(II) chloride) (0.05-1 eq.) with orwithout base (e.g., Cs₂CO₃, K₂CO₃, NaCO₃, Na₃PO₄, NaH₂PO₄, Na₂HPO₄,Et₃N, iPr₂NEt, t-BuOK, t-BuONa) were combined in DMF or dioxane, with orwithout water. The reaction was either heated to 100° C. to 200° C. insealed tube or carried out in the microwave synthesizer for 20 minutesto 72 hours. The mixture was diluted with MeOH and filtered. Thefiltration was concentrated and purified by HPLC or recrystallization tooffer 1-In-5.

General Process for the Preparation of Compound I-In-6 from 1-In-5:

1-In-5 was added into a solution TFA in dichloromethane (1% to 100%) orHCl in ether (2N). The reaction mixture was stirred at room temperaturefor 30 minutes to 18 hours. Concentration under vacuum provided aresidue which was purified by silica chromatography or HPLC to afford1-in-6.

General Process for the Preparation of Compound I from 1-In-6:

2-Keto acid (1 eq.), 1-In-6 (1-5 eq.), coupling agent (TBTU, DEPBT orBOP) (1-5 eq.) and Hunig's Base (1-100 eq.) were combined in DMF or THF.The mixture was stirred at room temperature for 17 hours. DMF or THF wasremoved via evaporation at reduced pressure and the residue waspartitioned between ethyl acetate and 5-10% Na₂CO₃ or 5% NaHCO₃ or NH₄Claqueous solution. The aqueous layer was extracted with ethyl acetate ormethylene chloride. The organic phase combined and dried over anhydrousMgSO₄. Concentration in vacuo provided a crude product, which waspurified by trituration, or recrystallization, or silica gel columnchromatography, or Shimadzu automated preparative HPLC system, to affordCompound I.

Characterization of 1-In and I (Table I):

TABLE I Compound MS (M + H)⁺ MS (M + H)⁺ Observ. and No. StructureCalcd. Retention Time and NMR I-In-1

188 188, Rf = 1.19 min (Method 2). ¹H NMR (500 MHz, CDCl₃) δppm 9.21(s,1H), 8.11(s, 1H), 7.94-8.08 (m, 2H). I-In-2

192 192, Rf = 0.24 min (Method 2). I-In-3

292 292, Rf = 2.99 min. (Method 2). ¹H NMR (500 MHz, CDCl₃): δppm7.20(s, 1 H), 4.71(s, 2H), 3.97- 4.07(m, 2H), 3.78-3.93 (m, 2H), 1.47(s,9H). I-In-4

370 ¹H NMR (500 MHz, CDCl₃): δppm 4.70(s, 2H), 3.91-3.90(m, 4H), 1.49(s, 9H). I-In-5a

368 368, Rf = 2.35 min. (Method 2). I-In-5b

369 369, Rf = 2.10 min (Method 3). I-In-6a

268 268, Rf = 1.67 min. (Method 2). I-In-6b

269 269, Rf = 1.39 min (Method 3). I1

551 551, Rf = 2.77 min (Method 2). ¹H NMR (500 MHz, DMSO-d₆): δppm12.45- 12.52(m, 1H), 9.22-9.27 (m, 1H), 8.30-8.38(m, 1H), 7.87-7.92(m,1H), 7.41-7.58(m, 5H), 4.74- 4.98(m, 2H), 3.74-4.14 (m, 10H). I2

525 525, Rf = 2.00 min (Method 1). ¹H NMR (500 MHz, DMSO-d₆): δppm13.07- 13.18(m, 1H), 8.99-9.06 (m, 1H), 8.42-8.61(m, 1H), 8.31-8.37(m,1H), 8.13(s, 1H), 7.41-7.59 (m, 5H), 4.79-4.98(m, 2H), 3.76-4.13(m, 4H).I3

552 552, Rf = 1.23 min (Method 4). ¹H NMR (500 MHz, DMSO-d₆): δppm2.51(s, 3H), 3.69-4.33(m, 7H), 4.71-5.16(m, 2H), 7.43- 7.71(m, 2 H),7.81-7.95 (m, 1H) 7.92-8.15(m, 1H) 8.19-8.48(m, 1H), 8.70(d, J = 4.27Hz, 1H), 9.24(s, 1H), 12.49(s, 1H).

Example J Preparation of Compounds J of Formula 1

Process for the Preparation of Compound J-In-2 from J-In-1:

To a stirred solution of 4,7-dimethoxy azaindole (1 eq.) in anisole wasadded phosphorus oxybromide (1 eq.) portion wise and the reactionmixture was slowly heated to 120° C. Reaction mixture was allowed tostir at 120° C. for about 18 h. Then, the reaction mixture was cooled to10° C. and slowly quenched with ice-water mixture. The resulting mixturewas neutralized with saturated sodium bicarbonate solution and thenextracted with ethyl acetate. The combined organic layer was washed withbrine, dried over sodium sulfate, filtered and concentrated. The crudeproduct was purified by column chromatography using 60-120 silica geland 15% ethyl acetate in hexane as eluent to afford J-In-2.

Process for the Preparation of Compound J-In-3 from J-In-2:

To a stirred solution of aluminum chloride (4 eq.) in drydichloromethane under nitrogen atmosphere was added J-In-2 (1 eq.)portion wise and the reaction mixture was stirred at room temperaturefor 2 h. In a separate flask, to a stirred solution of aluminum chloride(6 eq.) in dry dichloromethane under nitrogen atmosphere was addedmethoxy oxalylchloride (3 eq.) drop wise. The reaction mixture wasallowed to stir at room temperature for 2 hrs. Then this reactionmixture was added slowly to the above reaction mixture for about 30 minand stirred for 16 h at room temperature. The reaction mixture wasquenched with saturated ammonium acetate solution to pH-7. The resultingmixture was extracted with ethyl acetate. The combined organic layer waswashed with brine, dried over sodium sulfate, filtered and concentrated.The crude product was purified by column chromatography using 60-120silica gel and 25% ethyl acetate in hexane as eluent to afford J-In-3.

General Process for the Preparation of Compound J-In-4 from J-In-3:

J-In-3 (1 eq.) was dissolved in THF/water or acetone/water mixture(1:1), LiOH or NaOH or K₂CO₃ (2-10 eq.) and the reaction was stirred for20 h at room temperature. The volatiles were removed under reducedpressure and acidified the mixture using dilute HCl (pH˜6). Theresulting solid (J-In-4) was filtered, dried and used for the next stepwithout further purification.

General Process for the Preparation of Compound J-In-5 from J-In-4:

2-Keto acid (1 eq.), J-In-4 (1-5 eq.), coupling agent (TBTU, DEPBT orBOP) (1-5 eq.) and Hunig's Base (1-100 eq.) were combined in DMF or THF.The mixture was stirred at room temperature for 17 hours. DMF or THF wasremoved via evaporation at reduced pressure and the residue waspartitioned between ethyl acetate and 5-10% Na₂CO₃ or 5% NaHCO₃ or NH₄Claqueous solution. The aqueous layer was extracted with ethyl acetate ormethylene chloride. The organic phase combined and dried over anhydrousMgSO₄. Concentration in vacuo provided a crude product, which waspurified by trituration, or recrystallization, or silica gel columnchromatography, or Shimadzu automated preparative HPLC system, to affordJ-In-5.

General Process for the Preparation of Compound J from J-In-5:

J-In-5 (1 eq.), boronic or stannane agent (1-10 eq.) and palladiumcatalyst (e.g., tetrakis(triphenylphosphine)palladium,bis(diphenylphosphino)ferrocene palladium (II) chloride,bis(triphenylphosphine)palladium(II) chloride) (0.05-1 eq.) with orwithout base (e.g., Cs₂CO₃, K₂CO₃, NaCO₃, Na₃PO₄, NaH₂PO₄, Na₂HPO₄,Et₃N, iPr₂NEt, t-BuOK, t-BuONa) were combined in DMF or dioxane, with orwithout water. The reaction was either heated to 100° C. to 200° C. insealed tube or carried out in the microwave synthesizer for 20 minutesto 72 hours. The mixture was diluted with MeOH and filtered. Thefiltration was concentrated and purified by HPLC or recrystallization tooffer Compound J.

Characterization of J-In and J (Table J):

TABLE J Compound MS (M + H)⁺ MS (M + H)⁺ Observ. and No. StructureCalcd. Retention Time and NMR J-In-2

227 227. J-In-3

313 313. J-In-4

299 299. J-In-5

480 480. J1

498 498, Rf = 1.72 min (Method 2). ¹H NMR (500 MHz, MeOD): δppm4.08-4.22 (m, 5H), 4.30-4.46(m, 2H), 4.81(s, 2H), 5.23-5.40(m, 2H),7.19(s, 1H), 7.53-7.67 (m, 5H), 7.70-7.80(m, 1H), 7.99-8.07(m, 1H),8.68- 8.79(m, 1H). J2

526 526, Rf = 1.92 min (Method 2). ¹H NMR (500 MHz, MeOD): δppm 1.69(s,6H), 4.15(m, 5H), 4.29-4.48(m, 2H), 5.27-5.39(m, 2H), 7.14(s, 1H),7.54-7.69(m, 5H), 7.71-7.83(m, 1H), 8.04(s, 1H), 8.72-8.82(m, 1H).

Example K Preparation of Compounds K of Formula 1

General Process for the Preparation of Compound K-In-2 from K-In-1:

K-In-1 (1 eq.), base selected from Cs₂CO₃, K₂CO₃, NaCO₃, Na₃PO₄,NaH₂PO₄, Na₂HPO₄, Et₃N, iPr₂NEt, t-BuOK and t-BuONa (1-10 eq.), copperagent selected from Cu, CuCl, CuBr and CuI (0.01-2 eq.),(1R,2R)-diaminomethylcyclohexane (0.02-4 eq.), and aryl bromide or aryliodide (1-5 eq.) were combined in a sealable flask. The mixture wasdiluted with 1,4-dioxane. The flask was flushed with N₂, sealed, andheated to 100° C. for 2-24 h. The mixture was cooled to room temperatureand was filtered through a pad of CELITE® to remove solids. The organicsolution was concentrated under reduced pressure, and the residue waspurified by silica chromatography or HPLC to afford K-In-2.

General Process for the Preparation of Compound K-In-3 from K-In-2:

K-In-2 was added into a solution TFA in dichloromethane (1% to 100%) orHCl in ether (2N). The reaction mixture was stirred at room temperaturefor 30 minutes to 18 hours. Concentration under vacuum provided aresidue which was purified by silica chromatography or HPLC to affordK-In-3.

General Process for the Preparation of Compound K from K-In-3:

2-Keto acid (1 eq.), K-In-3 (1-5 eq.), coupling agent (TBTU, DEPBT orBOP) (1-5 eq.) and Hunig's Base (1-100 eq.) were combined in DMF or THF.The mixture was stirred at room temperature for 17 hours. DMF or THF wasremoved via evaporation at reduced pressure and the residue waspartitioned between ethyl acetate and 5-10% Na₂CO₃ or 5% NaHCO₃ or NH₄Claqueous solution. The aqueous layer was extracted with ethyl acetate ormethylene chloride. The organic phase combined and dried over anhydrousMgSO₄. Concentration in vacuo provided a crude product, which waspurified by trituration, or recrystallization, or silica gel columnchromatography, or Shimadzu automated preparative HPLC system, to affordCompound K.

Characterization of K-In and K (Table K):

TABLE K Compound MS (M + H)⁺ MS (M + H)⁺ Observ. and No. StructureCalcd. Retention Time and NMR K-In-2

376 376, Rf = 3.405 min (Method 2). ¹H NMR (500 MHz, CDCl₃): δppm7.77(d, J = 7.02 Hz, 2H), 7.26-7.61 (m, 8H), 4.75(br. s., 2H), 3.74(br.s., 2H), 2.85- 2.94(m, 2H), 1.48-1.55 (m, 9H). K-In-3

276 276, Rf = 2.06 min (Method 2). ¹H (500 MHz, MeOD): δppm 7.40-7.74(m,10H), 4.54(s, 2H), 3.60(t, J = 6.10 Hz, 2H), 3.20(t, J = 6.10 Hz, 2H).K1

559 559, Rf = 2.09 min (Method 1). ¹H NMR (500 MHz, DMSO-d₆): δppm 12.44(br. s., 1H), 9.21-9.28(m, 1H), 8.19-8.35(m, 1H), 7.27-7.98(m, 11H),4.73- 4.98(m, 2H), 3.70-4.04 (m, 5H), 2.91-3.12(m, 2H), 2.44-2.55(m,3H).

Example L Preparation of Compounds L of Formula 1

General Process for the Preparation of Compound L-In-1 from tert-Butyl3-((dimethylamino)methylene)-4-oxopiperidine-1-carboxylate:

tert-Butyl 3-((dimethylamino)methylene)-4-oxopiperidine-1-carboxylate (1eq.) and hydrazine (1-2 eq.) were mixed in ethanol. The reaction mixturewas heated at 115° C. for 16 h. After removal of the solvents undervacuum, the residue was purified using silica gel column chromatographyor Shimadzu automated preparative HPLC system, to afford L-In-1.

General Process for the Preparation of Compound L-In-2 from L-In-1:

L-In-1 was added to a solution of TFA in dichloromethane (1% to 100%) orHCl in ether (2N). The reaction mixture was stirred at room temperaturefor 30 minutes to 18 hours. Concentration under vacuum provided aresidue which was purified by silica chromatography or HPLC to affordL-In-2.

General Process for the Preparation of Compound L from L-In-2:

2-Keto acid (1 eq.), L-In-2 (1-5 eq.), coupling agent (TBTU, DEPBT orBOP) (1-5 eq.) and Hunig's Base (1-100 eq.) were combined in DMF or THF.The mixture was stirred at room temperature for 17 hours. DMF or THF wasremoved via evaporation at reduced pressure and the residue waspartitioned between ethyl acetate and 5-10% Na₂CO₃ or 5% NaHCO₃ or NH₄Claqueous solution. The aqueous layer was extracted with ethyl acetate ormethylene chloride. The organic phase combined and dried over anhydrousMgSO₄. Concentration in vacuo provided a crude product, which waspurified by trituration, or recrystallization, or silica gel columnchromatography, or Shimadzu automated preparative HPLC system, to affordCompound L.

Characterization of L-In and L (Table L):

TABLE L Compound MS (M + H)⁺ MS (M + H)⁺ Observ. and No. StructureCalcd. Retention Time and NMR L-In-1a

302 302, Rf = 1.72 min (Method 4). L-In-1b

330 330, Rf = 1.72 min (Method 4). L-In-1c

300 300, Rf = 1.91 min (Method 4). L-In-1d

301 301, Rf = 1.94 min (Method 4). L-In-1e

302 302, Rf = 1.86 min (Method 4). L-In-2a

202 202, Rf = 0.26 min (Method 10). L-In-2b

230 230, Rf = 0.46 min (Method 11). L-In-2c

200 200, Rf = 1.01 min (Method 12). L-In-2d

201 201, Rf = 0.65 min (Method 4). L-In-2e

202 202, Rf = 0.35 min (Method 10). L1

485 485, Rf = 1.48 min (Method 5). ¹H NMR (500 MHz, DMSO- d₆): δppm12.36-12.44 (m, 1H), 9.20-9.25 (m, 1H), 8.80- 8.92 (m, 2H), 8.17-8.30(m, 1H), 7.40-7.88 (m, 3H), 4.46-4.77 (m, 2H), 3.78- 3.97 (m, 5H),3.13-3.33 (m, 2H), 2.46 (s, 3H). L2

513 513, Rf = 1.49 min (Method 5). ¹H NMR (500 MHz, DMSO- d₆): δppm12.30-12.49 (m, 1H), 9.16-9.30 (m, 1H), 8.80- 8.32 (m, 1H), 7.55-7.88(m, 3H), 4.45-4.75 (m, 2H), 3.66-3.99 (m, 6H), 3.25- 3.44 (m, 3H),2.50-2.61 (m, 3H), 2.46-2.48 (m, 4H). L3

483 483, Rf = 1.69 min (Method 5). ¹H NMR (500 MHz, DMSO- d₆): δppm12.35-12.48 (m, 1H), 9.18-9.26 (m, 1H), 8.19- 8.33 (m, 1H), 7.82-7.90(m, 1H), 7.60-7.72 (m, 1H), 7.46-7.59 (m, 4H), 7.34- 7.40 (m, 1H),4.48-4.74 (m, 2H), 3.65-3.96 (m, 5H), 2.85- 3.04 (m, 2H), 2.47-2.48 (m,3H). L4

484 484, Rf = 1.68 min (Method 5). ¹H NMR (500 MHz, DMSO- d₆): δppm12.33-12.44 (m, 1H), 9.18-9.27 (m, 1H), 8.36- 8.50 (m, 1H), 8.17-8.29(m, 1H), 7.93-8.00 (m, 1H), 7.81-7.90 (m, 2H), 7.58- 7.77 (m, 1H),7.28-7.36 (m, J = 6.87, 5.34 Hz, 1H), 4.47- 4.73 (m, 2H), 3.68-3.97 (m,5H), 3.19-3.38 (m, 2H), 2.46- 2.48 (m, 3H). L5

485 485, Rf = 1.58 min (Method 5). ¹H NMR (500 MHz, DMSO- d₆): δppm12.34-12.44 (m, 1H), 9.15-9.26 (m, 2H), 8.44- 8.61 (m, 2H), 8.17-8.29(m, 1H), 7.68-7.89 (m, 2H), 4.48-4.77 (m, 2H), 3.68- 3.99 (m, 5H),2.70-3.20 (m, 2H), 2.46-2.48 (m, 3H).

Example M Preparation of Compounds M of Formula 1

General Process for the Preparation of Compound M-In-1 from4,5,6,7-Tetrahydro-1H-imidazo[4,5-c]pyridine:

4,5,6,7-Tetrahydro-1H-imidazo[4,5-c]pyridine (1 eq.) was dissolved inCH₂Cl₂ and treated with TEA (2-10 eq.), BOC-Anhydride (2 eq.) and acatalytic amount of DMAP (0.01-1 eq.) and the mixture was stirred atroom temperature for 1-7 days. The reaction mixture was quenched with 1NHCl, followed by extraction with CH₂Cl₂. The organic phase was driedover Na₂SO₄, filtered and concentrated. The crude product containingboth diboc-regioisomers drawn above was dissolved in MeOH and treatedwith ammonia in MeOH and the mixture was heated at 60° C. for 2-8 h.Removal of solvents under vacuum afforded M-In-1 which was purified bytrituration, or recrystallization, or silica gel column chromatography,or Shimadzu automated preparative HPLC system. The crude M-In-1 could beused in the further reaction without any purification.

General Process for the Preparation of Compound M-In-2 from M-In-1:

M-In-1 (1 eq.), boronic acid (1-5 eq.), pyridine (0.01-5 eq.),Cu(OAc)_(z) (0.01-2 eq.) and molecular sieves (4A) were stirred inCH₂Cl₂ at room temperature with open air for 1-10 days. The reactionmixture was filtered to remove solids and the filtrate was concentratedunder vacuum provided a residue which was purified by HPLC to affordM-In-2.

General Process for the Preparation of Compound M-In-3 from M-In-2:

M-In-2 was added into a solution TFA in dichloromethane (1% to 100%) orHCl in ether (2N). The reaction mixture was stirred at room temperaturefor 30 minutes to 18 hours. Concentration under vacuum provided aresidue which was purified by silica chromatography or HPLC to affordM-In-3.

General Process for the Preparation of Compound M from M-In-3:

2-Keto acid (1 eq.), M-In-3 (1-5 eq.), coupling agent (TBTU, DEPBT orBOP) (1-5 eq.) and Hunig's Base (1-100 eq.) were combined in DMF or THF.The mixture was stirred at room temperature for 17 hours. DMF or THF wasremoved via evaporation at reduced pressure and the residue waspartitioned between ethyl acetate and 5-10% Na₂CO₃ or 5% NaHCO₃ or NH₄Claqueous solution. The aqueous layer was extracted with ethyl acetate ormethylene chloride. The organic phase combined and dried over anhydrousMgSO₄. Concentration in vacuo provided a crude product, which waspurified by trituration, or recrystallization, or silica gel columnchromatography, or Shimadzu automated preparative HPLC system, to affordCompound M.

Characterization of M-In and M (Table M):

TABLE M Compound MS (M + H)⁺ MS (M + H)⁺ Observ. and No. StructureCalcd. Retention Time and NMR M-In-1a

224 224, Rf = 0.96 (Method 1). ¹H NMR (500 MHz, CDCl₃): δppm 7.57 (s,1H), 4.43 (brs, 2H), 3.66 (brs, 2H), 2.64 (brs, 2H), 1.42 (s, 9H).M-In-2a

300 300, Rf = 1.41 min (Method 1). ¹H NMR (500 MHz, CDCl₃): δppm 8.68(br. s., 1H), 7.32- 7.73 (m, 6H), 4.66 (br. s., 2H), 3.76 (br. s., 2H),2.60-2.80 (m, 2H), 1.37-1.60 (m, 12H). M-In-2b

301 ¹H NMR (500 MHz, CDCl₃): δ9.04 (s, 1H), 8.54 (m, 1H), 7.95 (m, 1H),7.57 (m, 1H), 7.44 (m, 1H), 4.62 (s, 2H). 3.74 (m, 2H), 3.00 (m, 2H),1.45 (s, 9H). M-In-3a

200 200, Rf = 0.77 min (Method 1). M1

483 483, Rf = 1.10 min (Method 1). ¹H NMR (500 MHz, MeOD): δppm 9.24 (s,1H), 8.82-9.05 (m, 1H), 8.29-8.42 (m, 1H), 7.88 (s, 1H), 7.52-7.74 (m,5H), 3-5.02 (m, 2H), 3.95- 4.07 (m, 3H), 3.83-4.23 (m, 2H), 2.78-2.99(m, 2H), 2.57 (s, 3H). M2

484 484, Rf = 1.15 min (Method 1). ¹H NMR (500 MHz, DMSO- d₆): δppm12.47 (s, 1H), 9.24 (s, 1H) 8.9-8.78 (m, 1H) 8.60- 8.58 (m, 1H),8.31-8.28 (m, 1H), 8.11-8.08 (m, 1H), 7.88- 7.80 (m, 2H) 7.54-7.51 (m,1H) 4.78-4.53 (m, 2H), 4.01- 3.73 (m, 3H), 3.84 (s, 3H), 2.5 (s, 3H).

Example N Preparation of Compounds N of Formula 1

General Process for the Preparation of Compound N-In-1 fromPyrazin-2-ylmethanamine.

To a solution of 2-(aminomethyl)pyrazine dihydrochloride (1 eq.)[prepared as described by Dhar, T. G. M. et al., Bioorg. Med. Chem.Lett., 17, 5019-5024 (2007)] and N,N-diisopropylethylamine (2-10 eq.) inDMF at 25° C. was added aroyl chloride (1-2 eq.), and the mixture wasstirred at 25° C. for 24 h. The resulting mixture was concentrated undervacuum, and the residue was dissolved in ethyl acetate. The solution waswashed with water and brine, dried over anhyd. sodium sulfate, filtered,and concentrated. Column chromatography on silica gel (elution: 0-50%ethyl acetate/methylene chloride) N-In-1.

General Process for the Preparation of Compound N-In-2 from N-In-1:

To a suspension of N-In-1 (1 eq.) in toluene at room temperature wasadded phosphorous oxychloride (1-10 eq.) dropwise. The resulting mixturewas heated at reflux for 2.5 h. After cooling to room temperature thereaction mixture was diluted with ethyl acetate and water. The phaseswere separated. The aqueous phase was adjusted to pH 7 employing aqueoussodium bicarbonate solution and then extracted with ethyl acetate. Thecombined organic phases were washed with water and brine, dried overanhyd. sodium sulfate, filtered, and concentrated. Column chromatographyon silica gel (elution: 0-5% isopropanol/chloroform) provided N-In-2.

General Process for the Preparation of Compound N-In-3 from N-In-2:

A mixture of N-In-2 (1 eq.) and 20% palladium hydroxide on carbon(0.01-0.5 eq.) in methanol was stirred at 25° C. under hydrogen gas(1.00 atm) for 26 h. The reaction mixture was filtered, and the filtratewas concentrated under vacuum to provide N-In-3.

General Process for the Preparation of Compound N from N-In-3:

2-Keto acid (1 eq.), N-In-3 (1-5 eq.), coupling agent (TBTU, DEPBT orBOP) (1-5 eq.) and Hunig's Base (1-100 eq.) were combined in DMF or THF.The mixture was stirred at room temperature for 17 hours. DMF or THF wasremoved via evaporation at reduced pressure and the residue waspartitioned between ethyl acetate and 5-10% Na₂CO₃ or 5% NaHCO₃ or NH₄Claqueous solution. The aqueous layer was extracted with ethyl acetate ormethylene chloride. The organic phase combined and dried over anhydrousMgSO₄. Concentration in vacuo provided a crude product, which waspurified by trituration, or recrystallization, or silica gel columnchromatography, or Shimadzu automated preparative HPLC system, to affordCompound N.

Characterization of N-In and N (Table N):

TABLE N Compound MS (M + H)⁺ MS (M + H)⁺ Observ. and No. StructureCalcd. Retention Time and NMR N-In-1a

214 214. ¹H-NMR (500 MHz, CDCl₃): δ8.69 (s, 1H), 8.53 (m, 2H), 7.84 (m,2H), 7.53- 7.44 (m, 3H), 4.83 (d, 1H, J = 4.9 Hz). N-In-2a

196 196. N-In-3a

200 200. N1

HRMS: 483.1888 HRMS: 483.1873. ¹H-NMR (500 MHz, DMSO-d₆): δ12.48 (br s,1H), 9.25 (s, 1H), 8.36- 8.31 (m, 1H), 7.90 (m, 1H), 7.80-7.73 (m, 2H),7.62- 7.57 (m, 3H), 7.45 (s, 2/3H), 7.27 (s, 1/3H), 5.00 (s, 4/3H), 4.84(s, 2/3H), 4.41 (m, 2/3H), 4.26 (m, 4/3H), 4.05 (m, 2/3H), 3.92 (s, 1H),3.88 (s, 2H), 3.86 (m, 4/3H), 2.50 (s, 3H). N2

HRMS: 519.1699 HRMS: 519.1689. ¹H-NMR (500 MHz, DMSO-d₆): δ12.46 (br s,1H), 9.24 (s, 1H), 8.34- 8.30 (m, 1H), 7.88-7.86 (m, 1H), 7.69-7.60 (m,1H), 7.50-7.40 (m, 1H), 7.29-7.21 (m, 1H), 7.10 (s, 2/3H), 6.94 (s,1/3H), 4.96 (s, 4/3H), 4.79 (s, 2/3H), 4.09 (m, 2/3H), 3.98 (m, 2/3H),3.91 (m, 4/3H), 3.84 (s, 1H), 3.81 (m, 4/3H), 3.77 (s, 2H), 2.50 (s,3H).

Example O Preparation of Compounds O of Formula 1

General Process for the Preparation of Compound O-In-1 frompiperazine-2-carboxylic acid:

A three necked round bottom flask was charged withpiperazine-2-carboxylic acid dihydrochloride (1 eq.), cupric carbonate(1.1 eq.) and water. The reaction mixture was refluxed for about 2 h andit was filtered through CELITE® bed. The deep blue color filtrate wascooled to 0° C. and added sodium bicarbonate (3.7 eq.) into the reactionmixture very slowly. The reaction mixture was stirred at 0° C. for 30min and benzyl chloroformate (1.5 eq.) was added to the reaction mixturevery slowly. The progress of the reaction was monitored by TLC. Afterconsumption of starting material, the reaction mixture was filtered anda pale blue solid was washed with cold water, ethanol and diethyl ether.The pale blue solid was taken up in water and concentrated hydrochloricacid was added. To this solution, H₂S gas was purged for 1 h understirring at room temperature. The excess H₂S gas was removed by purgingwith nitrogen for 30 min. The reaction mixture was filtered throughCELITE® bed and was washed with 1.5N HCl. The colorless filtrate wasconcentrated to afford desired O-In-1.

General Process for the Preparation of Compound O-In-2 from O-In-1:

A three necked round bottom flask was charged with O-In-1 (1 eq.),sodium hydroxide (2 eq.) and acetonitrile. The reaction mixture wascooled to 0° C. and Boc anhydride (1 eq.) was added into the reactionmixture very slowly. The reaction mixture was stirred at roomtemperature for 16 h. The progress of the reaction was monitored by TLC.After consumption of starting material, the reaction mixture was washedwith petroleum ether. The aqueous layer was acidified with citric acidto pH˜6 and extracted with dichloro methane. The combined organic layerwas washed with brine solution and dried over anhydrous sodium sulfate.The organic layer was filtered and concentrated to afford O-In-2.

General Process for the Preparation of Compound O-In-3 from O-In-2:

A three necked round bottom flask was charged with O-In-2 (1 eq.),triethyl amine (2 eq.) and dry dichloromethane under nitrogenatmosphere. The reaction mixture was cooled to 0° C. and methylchloroformate (1.3 eq.) was added into the reaction mixture very slowly.The reaction mixture was stirred at −10° C. for 30 min and furthercooled to −30° C. Ammonia gas was purged in the reaction mixture for 30min at −30° C. The reaction mixture was allowed to stir at roomtemperature for 16 h. After consumption of starting material, ice-coldwater was added to reaction mixture. The organic layer was separated andaqueous layer was extracted with dichloromethane. The combined organiclayers was washed with water, brine and dried over anhydrous sodiumsulfate. The organic layer was filtered and concentrated under reducedpressure. The resulting crude product was purified by columnchromatography using 60-120 silica gel and chloroform\methanol (6%) aseluant to afford O-In-3.

General Process for the Preparation of Compound O-In-4 from O-In-3:

A three necked round bottom flask was charged with O-In-3 (1 eq.) in dryTHF under nitrogen atmosphere. The reaction mixture was cooled to 0° C.and borane-dimethyl sulphide (4 eq.) was added into the reaction mixturevery slowly. The reaction mixture was allowed to stir at roomtemperature for 16 h. After consumption of starting material, methanolwas added to the reaction mixture very slowly. The reaction mixture wasstirred at room temperature for 30 min and evaporated to removevolatiles. The residue was dissolved in dichloromethane and ice coldwater. The organic layer was separated and aqueous layer was extractedwith dichloromethane. The combined organic layers was washed with water,brine and dried over anhydrous sodium sulfate. The organic layer wasfiltered and concentrated under reduced pressure. The resulting crudeproduct was purified by column chromatography using 60-120 silica geland chloroform\methanol (10%) as eluant to afford O-In-4.

General Process for the Preparation of Compound O-In-5 from O-In-4:

To O-In-5 dissolved in dry methanol, excess of methanolic HCl was addedat 0° C. The reaction mixture was allowed to stir at room temperaturefor 3 h. The volatiles were completely removed under vacuum to provideO-In-5 as an HCl salt which was used in the further reactions withoutany purification.

General Process for the Preparation of Compound O-In-6 from O-In-5:

To O-In-5 (1 eq.) dissolved in dry triethylamine, thiobenzamide (2 eq.)was added. The reaction mixture was heated to 100° C. for 3 h. Thevolatiles were completely removed under vacuum and the residue wasdiluted with water. The aqueous layer was extracted with dichloromethaneand the combined organic layer was washed with brine solution, driedover MgSO₄ and evaporated. The crude product was purified by columnchromatography using 60-120 silica gel and chloroform\methanol (8%) aseluant to afford O-In-6.

General Process for the Preparation of Compound O-In-7 from O-In-6:

Palladium on carbon (0.01-0.5 eq.) was added into the solution of O-In-6(1 eq.) in dry methanol under a nitrogen atmosphere. The reactionmixture was allowed to stir under a hydrogen atmosphere at 2 kg pressurefor 16 h. After the completion of the reaction, the reaction mixture wasfiltered through a CELITE® bed and washed repeatedly with methanol. Thefiltrate was concentrated under vacuum to afford O-In-7.

General Process for the Preparation of Compound O from O-In-7:

2-Keto acid (1 eq.), O-In-7 (1-5 eq.), coupling agent (TBTU, DEPBT orBOP) (1-5 eq.) and Hunig's Base (1-100 eq.) were combined in DMF or THF.The mixture was stirred at room temperature for 17 hours. DMF or THF wasremoved via evaporation at reduced pressure and the residue waspartitioned between ethyl acetate and 5-10% Na₂CO₃ or 5% NaHCO₃ or NH₄Claqueous solution. The aqueous layer was extracted with ethyl acetate ormethylene chloride. The organic phase combined and dried over anhydrousMgSO₄. Concentration in vacuo provided a crude product, which waspurified by trituration, or recrystallization, or silica gel columnchromatography, or Shimadzu automated preparative HPLC system, to affordCompound O.

Characterization of O-In and O (Table O):

TABLE O Compound MS (M + H)⁺ MS (M + H)⁺ Observ. and No. StructureCalcd. Retention Time and NMR O-In-1

265 265. ¹H NMR (400 MHz, DMSO- d₆): δ3.24 (m, 2H), 3.89 (m, 2H),4.14-4.20 (m, 2H), 5.11 (m, 1H), 7.30-7.42 (m, 5H), 9.86 (bs, 1H).O-In-2

(M − 1)⁺ 363 363 (M − 1)⁺. ¹H NMR (400 MHz, DMSO- d₆): δ1.40 (s, 9H),2.94 (m, 4H), 3.72-3.86 (m, 2H), 4.46 (m, 2H), 7.29-7.38 (m, 5H), 13.2(bs, 1H). O-In-3

364 ¹H NMR (400 MHz, DMSO- d₆): δ1.48 (s, 9H), 2.90 (m, 1H), 3.15-3.18(m, 2H), 3.6- 3.68 (m, 2H), 3.71-3.81 (m, 2H), 4.57-4.67 (m, 2H), 5.07-5.10 (dd, 2H), 7.29-7.38 (m, 5H). O-In-4

350 350. ¹H NMR (400 MHz, DMSO- d₆): δ1.48 (s, 9H), 2.90-3.1 (m, 2H),3.2-3.33 (m, 3H), 3.6-3.68 (d, 1H), 3.71-3.81 (dd, 1H), 4.35-4.45 (m,2H), 5.05 (s, 2H), 7.01 (bs, 1H), 7.35-7.38 (m, 5H). O-In-5

250 250. ¹H NMR (400 MHz, DMSO- d₆): δ2.90-3.1 (m, 2H), 3.18- 3.33 (m,3H), 3.5-3.65 (m, 2H), 3.94-4.02 (dd, 1H), 4.18- 4.23 (dd, 1H), 5.05 (s,2H), 7.35-7.44 (m, 5H), 8.5 (bs, 3H), 10.12 (bs, 2H). O-In-6a

336 336. ¹H NMR (400 MHz, DMSO- d₆): δ2.70-2.73 (m, 1H), 3.11- 3.18 (m,2H), 3.58-3.63 (m, 2H), 3.75-3.80 (m, 2H), 4.18- 4.22 (m, 2H), 5.05 (s,2H), 7.35-7.50 (m, 10H). O-In-6b

337 337. ¹H NMR (400 MHz, DMSO- d₆): δ3.18-3.23 (m, 3H), 3.41- 3.58 (m,2H), 3.6-3.65 (m, 2H), 4.10-4.14 (m, 2H), 5.05 (s, 2H), 7.35-7.44 (m,5H), 7.7 (m, 1H), 8.02-8.03 (m, 1H), 8.48-8.50 (d, 1H), 8.65- 8.66 (d,1H). O-In-7a

202 202. ¹H NMR (400 MHz, DMSO- d₆): δ3.05-3.10 (m, 2H), 3.21- 3.28 (m,2H), 3.58-3.65 (m, 2H), 3.70-3.73 (m, 1H), 3.9- 4.04 (m, 2H), 7.36-7.5(m, 5H). O-In-7b

203 203. ¹H NMR (400 MHz, DMSO- d₆): δ3.2-3.40 (m, 3H), 3.51- 3.60 (m,2H), 3.6-3.65 (m, 2H), 4.0-4.04 (m, 2H), 7.7 (m, 1H), 8.02-8.03 (m, 1H).8.48-8.50 (d, 1H), 8.65-8.66 (d, 1H). O1

459 459. ¹H NMR (400 MHz, DMSO- d₆): δ2.6 (m, 2H), 2.85-2.95 (m, 2H),3.10-3.15 (m, 1H), 3.5-3.69 (m, 4H), 3.8-4.01 (m, 2H), 4.17-4.43 (m,3H), 4.47 (dd, 1H), 7.17 (m, 1H), 7.40-7.60 (m, 2H), 7.70- 7.97 (m, 3H),8.04-8.09 (dd, 1H), 8.17-8.25 (m, 1H), 8.29- 8.32 (dd, 1H), 9.03 (m,1H). O2

486 486. ¹H NMR (400 MHz, DMSO- d₆): δ2.4 (s, 3H), 3.11-3.13 (m, 1H),3.49-3.59 (m, 3H), 3.6-3.69 (m, 1H), 4.01 (s, 3H), 4.17-4.43 (d, 2H),4.47 (dd, 1H), 7.77 (m, 1H), 7.89- 7.90 (d, 1H), 7.96-7.97 (m, 1H),8.14-8.27 (m, 1H), 8.27- 8.29 (d, 1H), 8.80-8.9 (dd, 1H), 9.23 (s, 1H),12.5 (bs, 1H).

Biology Data for the Examples

-   -   “μM” means micromolar    -   “mL” means milliliter    -   “μl” means microliter    -   “mg” means milligram

The materials and experimental procedures used to obtain the resultsreported in Tables 1-2 are described below.

Cells:

-   -   Virus production—Human embryonic Kidney cell line, 293T, was        propagated in Dulbecco's Modified Eagle Medium (Invitrogen,        Carlsbad, Calif.) containing 10% fetal Bovine serum (FBS, Sigma,        St. Louis, Mo.).    -   Virus infection—Human epithelial cell line, HeLa, expressing the        HIV-1 receptor CD4 was propagated in Dulbecco's Modified Eagle        Medium (Invitrogen, Carlsbad, Calif.) containing 10% fetal        Bovine serum (FBS, Sigma, St. Louis, Mo.) and supplemented with        0.2 mg/mL GENETICIN® (Invitrogen, Carlsbad, Calif.).    -   Virus—Single-round infectious reporter virus was produced by        co-transfecting human embryonic Kidney 293 cells with an HIV-1        envelope DNA expression vector and a proviral cDNA containing an        envelope deletion mutation and the luciferase reporter gene        inserted in place of HIV-1 nef sequences (Chen et al., Ref 41).        Transfections were performed using Lipofectamine Plus reagent as        described by the manufacturer (Invitrogen, Carlsbad, Calif.).        Experimental Procedure:

1. HeLa CD4 cells were plated in 96 well plates at a cell density of1×10⁴ cells per well in 100 μl Dulbecco's Modified Eagle Mediumcontaining 10% fetal Bovine serum and incubated overnight.

2. Compound was added in a 2 μl dimethylsulfoxide solution, so that thefinal assay concentration would be ≦10 μM.

3. 100 μl of single-round infectious reporter virus in Dulbecco'sModified Eagle Medium was then added to the plated cells and compound atan approximate multiplicity of infection (MOI) of 0.01, resulting in afinal volume of 200 μl per well.

4. Virally-infected cells were incubated at 37° C., in a CO₂ incubator,and harvested 72 h after infection.

5. Viral infection was monitored by measuring luciferase expression fromviral DNA in the infected cells using a luciferase reporter gene assaykit, as described by the manufacturer (Roche Molecular Biochemicals,Indianapolis, Ind.). Infected cell supernatants were removed and 50 μlof lysis buffer was added per well. After 15 minutes, 50 μl offreshly-reconstituted luciferase assay reagent was added per well.Luciferase activity was then quantified by measuring luminescence usinga Wallac MICROBETA® scintillation counter.

6. The percent inhibition for each compound was calculated byquantifying the level of luciferase expression in cells infected in thepresence of each compound as a percentage of that observed for cellsinfected in the absence of compound and subtracting such a determinedvalue from 100.

7. An EC₅₀ provides a method for comparing the antiviral potency of thecompounds of this disclosure. The effective concentration for fiftypercent inhibition (EC₅₀) was calculated with the Microsoft Excel Xlfitcurve fitting software. For each compound, curves were generated frompercent inhibition calculated at 10 different concentrations by using afour parameter logistic model (model 205). The EC₅₀ data for thecompounds is shown in Table 2. Table 1 is the key for the data in Table2.

Results

TABLE 1 Biological Data Key for EC₅₀s Compounds with EC₅₀s >0.5 μMCompounds with EC₅₀ <0.5 μM Group “B” Group “A”

TABLE 2 EC₅₀ Com- Group pound from No. Structure Table 1 A1

217 nM B1

0.95 nM B2

A B3

A B4

A C1

11.8 nM C2

0.29 nM C3

A C4

>500 nM C5

A C6

A C7

1.91 nM C8

A D1

A D2

0.05 nM D3

A E1

A F1

A F2

A F3

A F4

A F5

98.9 nM F6

13.6 nM G1

A G2

A H1a

A H1b

A H2

1 nM I1

A I2

A I3

0.59 nM J1

0.05 nM J2

A K1

2.6 nM L1

A L2

331 nM L3

0.03 nM L4

A L5

A M1

0.07 nM M2

A N1

0.06 nM N2

A O1

13 nM O2

A

The foregoing description is merely illustrative and should not beunderstood to limit the scope or underlying principles of the inventionin any way. Indeed, various modifications of the invention, in additionto those shown and described herein, will become apparent to thoseskilled in the art from the following examples and the foregoingdescription. Such modifications are also intended to fall within thescope of the appended claims.

What is claimed is:
 1. A compound of Formula I or pharmaceuticallyacceptable salts thereof:

wherein A is

wherein B is

and further wherein a is methoxy; b is H; d is triazolyl; wherein saidtriazolyl is independently optionally substituted with one to three sameor different halogens or from one to three same or differentsubstituents selected from Group E; e is H; f and g are H; h and i areH; j and k are H; Ar is selected from the group consisting of phenyl andpyridinyl; wherein said phenyl and pyridinyl are independentlyoptionally substituted with one to three same or different halogens orfrom one to three same or different substituents selected from Group E;Group E is selected from the group consisting of OH, OR, NR₁R₂, CN,COOR, CONR₁R₂, (C₁ ⁻C₄) alkyl, (C₃-C₆) cycloalkyl, and wherein saidalkyl or cycloalkyl group is optionally substituted with one to threesubstituents selected from the group consisting of F, OH, OR, NR₁R₂,COOR, and CONR₁R₂; and R, R₁ and R₂ are independently H, (C₁-C₄) alkyl,or a (C₃-C₆) cycloalkyl group.
 2. A compound which is selected from thegroup consisting of:


3. A compound which is selected from the group consisting of


4. A pharmaceutical composition which comprises an antiviral effectiveamount of one or more of the compounds of Formula I as claimed in claim1, together with one or more pharmaceutically acceptable carriers,excipients or diluents.
 5. A pharmaceutical composition which comprisesan antiviral effective amount of one or more of the compounds of FormulaI as claimed in claim 2, together with one or more pharmaceuticallyacceptable carriers, excipients or diluents.
 6. A pharmaceuticalcomposition which comprises an antiviral effective amount of one or moreof the compounds of Formula I as claimed in claim 3, together with oneor more pharmaceutically acceptable carriers, excipients or diluents.